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LASSA FEVER

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Lassa fever is a viral hemorrhagic fever caused by an RNA virus (Lassa virus), a pantropic virus, of the Arenaviridae family. Lassa fever can be a highly fatal septicemic viral disease.

Specific Substances

    1) Lassa virus

Available Forms Sources

    A) USES
    1) Lassa 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 (CDC, 1999; PB Jahrling , 1997). The virus has been shown to be stable in aerosol, especially at low humidity (Nzerue, 1992).

Overview

Life Support

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

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) DESCRIPTION: Lassa fever is a viral hemorrhagic fever that has an affinity for many tissues and can be a highly fatal septicemic viral disease. It is an enveloped, single-stranded RNA virus endemic in the rodent population in Africa. Transmission from the Natal multimammate mouse (Mastomys natalensis) to humans probably occurs via contamination of superficial wounds by rodent urine or fecal matter. Human-to-human transmission requires close personal contact or contact with blood, secretions, or excreta and mucus membranes. Lassa 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. The virus has been shown to be stable in aerosol, especially at low humidity.
    B) EPIDEMIOLOGY: Lassa fever is named after a small town in northeastern Nigeria. It is endemic to much of West Africa and parts of Central Africa, and first recognized in 1969. There have been at least 10 instances of Lassa fever exported into countries outside of Africa, but no secondary transmission from these cases has been documented. It occurs more commonly in rural areas and more frequently in the dry compared to the rainy season. An estimated 100,000 to 300,000 cases occur in West Africa every year with approximately 5,000 related deaths.
    C) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: After an incubation period of approximately 10 to 14 days, illness often begins insidiously. Most patients (about 80%) are undiagnosed or develop only mild symptoms. Early symptoms can include fever, pharyngitis, weakness, and malaise. Pains in the joints and lower back, headache, and a nonproductive cough commonly follows. Other common symptoms include abdominal discomfort, retrosternal or epigastric pain, vomiting and diarrhea. In milder cases, the patients begin to recover after the first week of illness (within 8 to 10 days of disease onset). Duration of illness is usually 1 to 4 weeks.
    2) SEVERE TOXICITY: In more serious cases, the clinical condition continues to deteriorate. In about one-third of cases, various degrees of permanent sensorineural deafness results. Some patients may develop hemorrhage from gums, eyes, or nose, respiratory distress, persistent vomiting, facial swelling, pain in the chest, back, and abdomen, encephalopathy, hypotension and shock. Multiorgan failure may develop with death occurring within 2 weeks after symptom onset. The overall case fatality rate is 1% to 2%. Among those hospitalized with Lassa fever, the mortality rate is 15% to 20%. During an epidemic, mortality rate can reach 50% in hospitalized patients. The prognosis is particularly poor for women in the third trimester of pregnancy, and a high rate of fetal wastage occurs.
    0.2.20) REPRODUCTIVE
    A) Pregnant women are at particular risk of severe infection. The prognosis is particularly poor for women in the third trimester of pregnancy, and a high rate of fetal wastage occurs. Spontaneous abortion is common. Infection in the first trimester of pregnancy is associated with lower mortality compared to later in pregnancy.

Laboratory Monitoring

    A) No specific studies are needed for most patients. Tests should be directed towards a patient's symptoms.
    B) Monitor fluid and serum electrolytes in patients with significant vomiting and/or diarrhea; intravascular volume loss may be significant.
    C) Monitor vital signs and mental status as indicated. Monitor for evidence of encephalopathy and seizures.
    D) Nonspecific laboratory abnormalities include proteinuria and elevated liver enzymes, with AST levels exceeding those of ALT. The combination of proteinuria, fever, pharyngitis, and chest pain appears to be a good diagnostic predictor of Lassa fever in endemic areas.
    E) Monitor CBC with differential and platelet count.
    F) Definitive diagnosis of Lassa fever can be made by isolating the virus from blood, urine or throat washings and then demonstrating the presence of immunoglobulin M (IgM) antibody to Lassa virus or showing a 4-fold rise in titer of IgG antibody between acute- and convalescent-phase serum specimens. In the early stages of the disease, reverse transcription-polymerase chain reaction (RT-PCR) can be performed. In a high containment laboratory, the Lassa virus can be cultured in 7 to 10 days. A postmortem diagnosis can be made using immunohistochemistry which is performed on formalin-fixed tissue specimens.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) Treatment should include recommendations listed in the DERMAL EXPOSURE section when appropriate.
    0.4.3) INHALATION EXPOSURE
    A) Treatment should include recommendations listed in the DERMAL EXPOSURE section when appropriate.
    B) Although arenaviruses are not known to be casually transmitted from human-to-human via inhalation, researchers have shown a potential of aerosol infection by Lassa virus administered into the respiratory tract via inhalation. Use of Lassa virus as a biological warfare agent has been proposed due to its contagious and lethal properties. Medical personnel working with known Lassa 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.
    0.4.4) EYE EXPOSURE
    A) Treatment should include recommendations listed in the DERMAL EXPOSURE section when appropriate.
    B) Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes.
    0.4.5) DERMAL EXPOSURE
    A) OVERVIEW
    1) MANAGEMENT OF MILD TO MODERATE TOXICITY
    a) The mainstay of treatment is symptomatic and supportive care. Treat patients with Lassa fever with ribavirin. It has been shown to prevent death from Lassa fever when given at any stage in the disease. High risk contacts (unprotected contact with patient's body fluids or excretions) should receive prophylaxis with ribavirin therapy. They should also record their temperatures twice daily for 3 weeks postexposure. If they develop a fever (greater than 101 degrees F) or other systemic symptoms within 3 weeks of exposure, they should receive further medical evaluation.
    2) MANAGEMENT OF SEVERE TOXICITY
    a) The mainstay of treatment is good supportive care. Patients may require aggressive treatment for sepsis, including fluids and pressors for hypotension and intubation and ventilation for respiratory symptoms. Management of shock can be difficult. Response to fluid infusions is often poor, and these patients can readily develop pulmonary edema. Seizures may be treated with benzodiazepines, barbiturates, and/or propofol.
    3) DECONTAMINATION
    a) ORAL EXPOSURE: Oral decontamination measures following exposure to Lassa virus have not been proven to be effective.
    b) INHALATIONAL EXPOSURE: Although arenaviruses are not known to be casually transmitted from human-to-human via inhalation, researchers have shown a potential of aerosol infection by Lassa virus administered into the respiratory tract via inhalation. Use of Lassa virus as a biological warfare agent has been proposed due to its contagious and lethal properties. Medical personnel working with known Lassa 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.
    c) DERMAL EXPOSURE: Remove contaminated clothing immediately. Sites exposed to blood/body fluids should be immediately washed with soap and water.
    d) EYE EXPOSURE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes.
    e) FIRST RESPONDERS: Any healthcare personnel should follow strict isolation precautions (ie, includes gloves, gown, mask) and avoid direct contact with blood or bodily fluids of a patient with suspected Lassa fever.
    4) AIRWAY MANAGEMENT
    a) In cases of airway compromise, supportive measures including endotracheal intubation and mechanical ventilation may be necessary.
    5) ANTIDOTE
    a) None.
    6) PATIENT DISPOSITION
    a) HOME CRITERIA: All patients with suspected Lassa fever should be referred to a hospital for further observation, treatment, and isolation to prevent further spread. Close contacts of filovirus-infected patients should be stringently monitored and asked to report any fever (ie, record temperature twice daily for 3 weeks). Casual contacts with Lassa virus-infected patients should be placed on alert and asked to report any fever.
    b) OBSERVATION CRITERIA: Any person who has a history of close physical contact with an infected patient(s) should be under strict surveillance (ie, obtain temperature twice daily; in the case of a temperature greater than 38.3 degrees C (101 degrees F), hospitalize the patient immediately in strict isolation). Surveillance should be continued for 3 weeks after the date of the last contact. Hospital personnel who come in close contact with patients or contaminated material without barrier attire should be considered exposed and put under close, supervised surveillance. High risk contacts (unprotected contact with patient's body fluids or excretions) should receive prophylaxis with ribavirin therapy.
    c) ADMISSION CRITERIA: All patients with suspected Lassa fever should be admitted to the hospital for further observation, treatment, and isolation to prevent further spread.
    d) CONSULT CRITERIA: An infectious disease specialist should be consulted and involved in the care of all cases. Critically ill patients may require the services of an intensivist. All confirmed and suspected cases should be reported immediately through local and State health departments to the Viral Special Pathogens Branch of the Centers for Disease Control (CDC).
    7) PITFALLS
    a) Since Lassa fever is so rare, the diagnosis can be easily missed as many other infectious diseases can mimic the initial clinical manifestations of Lassa fever. It has been considered as a potential bioweapon.
    8) PREDISPOSING CONDITIONS
    a) The prognosis is particularly poor for women in the third trimester of pregnancy, with a high rate of spontaneous abortion (up to 95%).
    9) DIFFERENTIAL DIAGNOSIS
    a) Clinical manifestations of Lassa fever can be caused by many other infectious diseases that can cause similar nonspecific symptoms of infection.

Range Of Toxicity

    A) TOXICITY: As few as 1 to 10 organisms are capable of causing infection. The overall case fatality rate is about 1% to 2%. Among those hospitalized with Lassa fever, the mortality rate is 15% to 20%. During an epidemic, mortality rate can reach 50% in hospitalized patients. Poor prognostic indicators include elevated AST (greater than 150 International Units/L) with high viremia.

Clinical Effects

Summary Of Exposure

    A) DESCRIPTION: Lassa fever is a viral hemorrhagic fever that has an affinity for many tissues and can be a highly fatal septicemic viral disease. It is an enveloped, single-stranded RNA virus endemic in the rodent population in Africa. Transmission from the Natal multimammate mouse (Mastomys natalensis) to humans probably occurs via contamination of superficial wounds by rodent urine or fecal matter. Human-to-human transmission requires close personal contact or contact with blood, secretions, or excreta and mucus membranes. Lassa 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. The virus has been shown to be stable in aerosol, especially at low humidity.
    B) EPIDEMIOLOGY: Lassa fever is named after a small town in northeastern Nigeria. It is endemic to much of West Africa and parts of Central Africa, and first recognized in 1969. There have been at least 10 instances of Lassa fever exported into countries outside of Africa, but no secondary transmission from these cases has been documented. It occurs more commonly in rural areas and more frequently in the dry compared to the rainy season. An estimated 100,000 to 300,000 cases occur in West Africa every year with approximately 5,000 related deaths.
    C) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: After an incubation period of approximately 10 to 14 days, illness often begins insidiously. Most patients (about 80%) are undiagnosed or develop only mild symptoms. Early symptoms can include fever, pharyngitis, weakness, and malaise. Pains in the joints and lower back, headache, and a nonproductive cough commonly follows. Other common symptoms include abdominal discomfort, retrosternal or epigastric pain, vomiting and diarrhea. In milder cases, the patients begin to recover after the first week of illness (within 8 to 10 days of disease onset). Duration of illness is usually 1 to 4 weeks.
    2) SEVERE TOXICITY: In more serious cases, the clinical condition continues to deteriorate. In about one-third of cases, various degrees of permanent sensorineural deafness results. Some patients may develop hemorrhage from gums, eyes, or nose, respiratory distress, persistent vomiting, facial swelling, pain in the chest, back, and abdomen, encephalopathy, hypotension and shock. Multiorgan failure may develop with death occurring within 2 weeks after symptom onset. The overall case fatality rate is 1% to 2%. Among those hospitalized with Lassa fever, the mortality rate is 15% to 20%. During an epidemic, mortality rate can reach 50% in hospitalized patients. The prognosis is particularly poor for women in the third trimester of pregnancy, and a high rate of fetal wastage occurs.

Vital Signs

    3.3.2) RESPIRATIONS
    A) Increased respirations and pulse are common presenting signs of illness (Cummins, 1990; McCormick et al, 1987).
    3.3.3) TEMPERATURE
    A) After an incubation period of about 10 to 14 days, onset of illness is insidious, with persistent fever and malaise. Patients often present at hospital with profuse sweating and tachycardia, which is commensurate to the degree of pyrexia (Nzerue, 1992; McCormick et al, 1987).
    B) INCIDENCE - Virtually 100% of patients will have fever (Webb et al, 1986; Knobloch et al, 1980).
    3.3.4) BLOOD PRESSURE
    A) Decreased blood pressure is a common presenting sign of Lassa fever (McCormick et al, 1987).
    3.3.5) PULSE
    A) Patients with early onset of illness (first week) often present to the hospital with tachycardia, which is commensurate to the degree of fever (Nzerue, 1992; Cummins, 1990).

Heent

    3.4.2) HEAD
    A) In more severe cases (second week), stridor and tissue edema involving the head, neck and larynx may occur and is common, but peripheral edema is not usually seen (Nzerue, 1992; Cummins, 1990; McCormick et al, 1987). In children, the "swollen baby syndrome" is highly diagnostic of Lassa fever, and is identified by a triad of widespread edema (puffiness of face and neck, or "anasarca"), abdominal distention, and bleeding (Monson et al, 1987).
    3.4.3) EYES
    A) Conjunctivitis is common in the early stage of illness (first week) and is seen in about one-third of patients. Less commonly, conjunctival hemorrhages may occur during the second week of illness and are a poor prognostic sign (Nzerue, 1992; Frame, 1992; Cummins, 1990; McCormick et al, 1987; Knobloch et al, 1980).
    B) Uveitis is a complication during the later, more severe stages of illness (Nzerue, 1992).
    3.4.4) EARS
    A) Hearing deficits, thought to be immune-mediated, occur in the convalescent stage (10 to 15 days after disease onset) and are a frequent sequela of Lassa fever. In endemic areas, this is an important cause of deafness, with complete deafness being irreversible (PB Jahrling , 1997; Nzerue, 1992; Liao et al, 1992; Cummins, 1990; McCormick et al, 1987; Knobloch et al, 1980).
    1) INCIDENCE: Approximately one-third of Lassa fever cases experience various degrees of deafness, with hearing loss permanent in many cases. Severity of disease does not affect deafness; it may develop in mild as well as in severe cases (Centers for Disease Control and Prevention, 2015; CDC , 2000; Liao et al, 1992).
    3.4.5) NOSE
    A) Epistaxis and bleeding gums often occur in patients with more severe disease (McCormick et al, 1987).
    3.4.6) THROAT
    A) Exudative pharyngitis and cough are common presenting signs and symptoms during the first week of illness. About two-thirds of patients develop a dry, nonproductive cough by the third or fourth day of illness and about 70% of patients develop pharyngitis (McCormick, 1988; McCormick et al, 1987; Fabiyi, 1976). Sore throat and pharyngitis appear less frequently in children than in adults (Webb et al, 1986). Mucosal hemorrhages may occur during the second week of illness (Nzerue, 1992). Sore throat resolves within 8 to 10 days in mild cases.
    1) INCIDENCE - Out of 42 Lassa fever cases, 69% experienced coughing and 60% reported sore throat (Knobloch et al, 1980).
    B) Bleeding gums often occurs in patients with more severe disease (McCormick et al, 1987).
    C) Stridor due to laryngeal edema may occur (Cummins, 1990).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) HYPOTENSIVE EPISODE
    1) Dominant clinical features of Lassa fever include a consequence of microvascular damage and changes in vascular permeability, leading to severe hypotension and shock (Franz et al, 1997). Fulminant courses of Lassa fever result in marked hypovolemic shock which is resistant to fluids and pressor agents (Nzerue, 1992; Knobloch et al, 1980). Often, these patients respond poorly to fluid infusions and readily develop pulmonary edema (Franz et al, 1997).
    2) Severe disease is often associated with bleeding (usually mucosal), but the bleeding is almost never of a magnitude by itself to produce shock (McCormick et al, 1987).
    B) MYOCARDITIS
    1) Myocarditis is rare, but may occur in the later stages of illness. Nonspecific ECG changes have been described (Nzerue, 1992; Knobloch et al, 1980).
    C) PERICARDITIS
    1) Serositis supervenes about the second week of illness, with marked substernal chest pains and pleuropericardial rubs, sometimes with effusions. During the convalescence period, pericarditis tends to occur (Nzerue, 1992). Pleural and pericardial effusions may indicate a poor prognosis (Knobloch et al, 1980). One case of subacute effusive constrictive pericarditis accompanied by bilateral atrioventricular annular constriction due to Lassa fever is reported (Yanase et al, 1989).
    D) CHEST PAIN
    1) Substernal chest pains may begin during the second week of illness. Recovery from mild cases begins within 8 to 10 days with resolution of chest pain (Nzerue, 1992). Out of 42 Lassa fever cases, 62% reported chest pain (Knobloch et al, 1980).
    E) ELECTROCARDIOGRAM ABNORMAL
    1) In a case series of 32 Lassa fever patients, ECGs were abnormal in over 70%, with changes including non-specific ST-segment and T-wave abnormalities, ST-segment elevation, generalized low-voltage complexes, and changes reflecting electrolyte disturbance. No abnormalities correlated with clinical severity of illness, liver enzyme levels, or eventual outcome. ECG abnormalities were usually not associated with clinical manifestations of myocarditis (Cummins et al, 1989).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) ACUTE LUNG INJURY
    1) Adult respiratory distress syndrome (ARDS) may commonly result during the second week of illness in serious, fulminant cases (Nzerus, 1992). More severe Lassa fever progresses to respiratory distress with stridor between the sixth and tenth days due to laryngeal edema (McCormick et al, 1987). Dyspnea can be severe and may be associated with central cyanosis and pulmonary crepitations (Cummins, 1990).
    2) Noncardiogenic pulmonary edema is common during the end stage of severe illness and may occur during therapy with fluid replacement (Nzerue, 1992; Frame, 1992; Monson et al, 1987).
    B) PNEUMONITIS
    1) Approximately 20% of patients have been reported to develop dry diffuse rales associated with an interstitial pneumonitis. Pleural and pericardial effusions are not uncommon and are seen late in disease, at the beginning of convalescence, occasionally in association with congestive cardiac failure (McCormick et al, 1987), as well as in postmortem studies (Ikerionwu et al, 1978).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) TOXIC ENCEPHALOPATHY
    1) Unlike other viral hemorrhagic fevers, neurological complications from Lassa fever are infrequent (Franz et al, 1997; PB Jahrling , 1997; McCormick et al, 1987). A fulminant course of Lassa fever may include encephalitis (with or without generalized seizures and/or coma) during the second week of illness, and is a poor prognostic factor (CDC , 2000; Nzerue, 1992; McCormick et al, 1987). Encephalopathy generally presents as confusion and generalized tremor, followed by rapid deterioration of consciousness (over 6 to 8 hours), seizures and death; focal neurological signs are rare (Cummins, 1990).
    2) CASE SERIES - Acute encephalopathy was reported in 9 Lassa fever patients. Signs and symptoms of encephalopathy developed 3 to 17 days after disease onset; these included confusion, tremor (7 patients), tonic-clonic seizures (7 patients), abnormal posturing (3 patients) and coma (8 patients). Eight patients died (respiratory arrest). No direct correlation was made between development of encephalopathy and presence of virus in CSF or in serum (Cummins et al, 1992).
    B) HEADACHE
    1) Severe headache (more frontal than occipital) is a common presenting sign of Lassa fever and occurs in a majority of cases. Recovery from mild disease begins within 8 to 10 days with resolution of fever and headache (Nzerue, 1992; McCormick et al, 1987). Out of 42 Lassa fever cases, 57% reported headache (Knobloch et al, 1980).
    C) SEIZURE
    1) Seizures and tremors may occur as a neurological effect of severe illness (CDC , 2000). Neurological complications of seizures, unconsciousness and alterations in mental status indicate a poor prognosis (Knobloch et al, 1980). Febrile seizures may occur, particularly in children (Sharp, 1982).
    2) INCIDENCE - Out of 42 Lassa fever cases, fewer than 10% experienced seizures (Knobloch et al, 1980).
    D) HEARING LOSS
    1) A significant sequela of Lassa fever is neurosensory hearing loss. Approximately one-third of Lassa fever cases experience various degrees of deafness, with hearing loss permanent in many cases. Severity of disease does not affect deafness nor subsequent recovery; it may develop in mild as well as in severe cases. It is proposed that the sensorineural deafness is a virally-induced immune response mechanism (CDC , 2000; Liao et al, 1992; Nzerue, 1992; Cummins, 1990).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA, VOMITING AND DIARRHEA
    1) Nausea, vomiting and bloody diarrhea, sometimes profuse, often follows the initial illness and occurs in one-half to two-thirds of patients by the fifth day of illness. Fluid losses can be significant (McCormick, 1988; McCormick et al, 1987; McCormick, 1986; Knobloch et al, 1980).
    2) INCIDENCE: Out of 42 Lassa fever cases, approximately 37% were reported to have vomiting and/or diarrhea and 21% experienced bloody diarrhea (Knobloch et al, 1980). Out of 26 confirmed pediatric Lassa fever cases, vomiting and diarrhea were present in 62% and 35%, respectively (Webb et al, 1986).
    B) GASTROINTESTINAL HEMORRHAGE
    1) Gastrointestinal hemorrhages may occur during fulminant, latter stages of illness (Knobloch et al, 1980).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) HEPATIC NECROSIS
    1) In human fatalities, the most consistent lesions found were focal necrosis of liver, spleen and adrenal glands (Nzerue, 1992; Fisher-Hoch & McCormick, 1987; McCormick et al, 1986a; Knobloch et al, 1980). The characteristic liver findings are referred to as Lassa virus hepatitis (Winn et al, 1975). Hepatic failure has NOT been implicated as a cause of death; evidence of hepatocyte regeneration is seen.
    2) The most significant pathological findings at postmortem examination are eosinophilic necrosis of hepatocytes and spleen (Walker et al, 1982; Ikerionwu et al, 1978; Winn et al, 1975).
    B) LIVER ENZYMES ABNORMAL
    1) Hyperbilirubinemia and elevated liver enzymes are common, but clinical jaundice is rare (Franz Et al, 1997; (Johnson et al, 1987; McCormick, 1986). Levels of aspartate aminotransferase (AST) are of prognostic significance, with levels above 150 IU/L and high viremia during hospitalization being poor prognostic factors (Nzerue, 1992; Johnson et al, 1987; McCormick, 1986).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) ALBUMINURIA
    1) Proteinuria is reported in approximately two-thirds of patients with Lassa fever and may be persistent (Nzerue, 1992; Cummins, 1990; McCormick et al, 1987). The combination of fever, pharyngitis, chest pain, and proteinuria appears to be a good diagnostic predictor of Lassa fever in endemic areas (McCormick et al, 1987).
    B) ORCHITIS
    1) A rare complication of later stages of Lassa fever is orchitis (Nzerue, 1992; Anon, 1989).
    C) LACK OF EFFECT
    1) Unlike other hemorrhagic viral infections, renal failure is NOT seen with Lassa fever infections (Nzerue, 1992). Serum creatinine and BUN levels may be elevated due to severe dehydration (McCormick et al, 1987).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) HEMORRHAGE
    1) Unlike other viral hemorrhagic fevers, hemorrhagic manifestations are NOT pronounced for Lassa fever (Franz et al, 1997; PB Jahrling , 1997). Fulminant cases will develop hemorrhage during the second week of illness (Nzerue, 1992; Knobloch et al, 1980). Hemorrhage, which has occurred in about 20% of hospitalized patients, is most evident from the gingival mucosae, but can occur from other sites and is rarely of a magnitude by itself to cause shock. Presence of hemorrhage is a poor prognostic sign (Cummins, 1990; Frame, 1989).
    a) Hematocrit levels are often elevated due to dehydration (Cummins, 1990; McCormick et al, 1987). Bleeding does NOT appear to be due to thrombocytopenia; rather, damage of the blood vessels and/or functional defects of platelets are likely causes of hemorrhage (Knobloch et al, 1980).
    2) Clinical signs/symptoms are more compatible with capillary leakage than with impaired venous return (McCormick et al, 1987).
    B) THROMBOCYTOPENIC DISORDER
    1) Thrombocytopenia is uncommon, but when present, is generally mild and found in severe Lassa fever (Nzerue, 1992; Fisher-Hoch et al, 1988), and there is no or rare evidence of disseminated intravascular coagulation (Frame, 1989; McCormick et al, 1987; Fisher-Hoch & McCormick, 1987). Patients with fulminant infection have shown a marked inhibition of ADP-induced platelet aggregation; the presence of inhibitor appears to be strongly associated with the occurrence of hemorrhage, depression of platelet aggregation and severity of Lassa fever (Cummins et al, 1989a).
    C) LEUKOCYTOSIS
    1) Leukocytosis and neutrophilia are commonly reported in severe cases (Nzerue, 1992; Monson et al, 1987) and may occur in the early stages of illness (Anon, 1983; Cooper et al, 1982).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) EDEMA
    1) Tissue edema, described as pitting edema, during the second week of illness may be common and can be severe. Edema is usually confined to the head (face) and neck; in women breast edema may develop (Centers for Disease Control and Prevention, 2015; Cummins, 1990; Frame, 1989; Monson et al, 1987). Peripheral edema is NOT usually seen. Ascites is a marked complication of later stages of Lassa fever (Nzerue, 1992; McCormick et al, 1987).
    B) ERUPTION
    1) The occurrence of rash during Lassa fever is rare (Nzerue, 1992). Skin purpura is rare (Knobloch et al, 1980). One case of a maculopapular rash that covered the trunk and extremities was reported; it improved following recovery from Lassa fever (Anon, 1989).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) MUSCLE PAIN
    1) In the early stages of illness (by third or fourth day of illness) patients often present with generalized myalgia and backache (Nzerue, 1992; McCormick et al, 1987). More than half of the Lassa fever cases report myalgia (McCormick et al, 1987; Knobloch et al, 1980).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) INFECTIOUS DISEASE
    1) The spectrum of Lassa virus infection ranges from a subclinical infection to a severe, at times fatal, infection accompanied by high fever, viremia, viruria, hemodynamic alterations, and cardiovascular collapse (Buckley & Casals, 1978).
    B) HEARING LOSS
    1) Hearing deficits, thought to be immune-mediated, occur in the convalescent stage. In endemic areas, this is an important cause of deafness, with complete deafness being irreversible (Centers for Disease Control and Prevention, 2015; Nzerue, 1992; Liao et al, 1992; Cummins, 1990; Knobloch et al, 1980).
    2) INCIDENCE: Approximately one-third of Lassa fever cases experience various degrees of deafness, with hearing loss permanent in many cases. Severity of disease does not affect deafness; it may develop in mild as well as in severe cases (CDC , 2000).
    C) LYMPHADENOPATHY
    1) Enlarged cervical lymph nodes may occur in the early stages of illness (first week) (Sharp, 1982).

Reproductive

    3.20.1) SUMMARY
    A) Pregnant women are at particular risk of severe infection. The prognosis is particularly poor for women in the third trimester of pregnancy, and a high rate of fetal wastage occurs. Spontaneous abortion is common. Infection in the first trimester of pregnancy is associated with lower mortality compared to later in pregnancy.
    3.20.3) EFFECTS IN PREGNANCY
    A) INFECTION
    1) Pregnant women are at particular risk of severe infection. The prognosis is particularly poor for women in the third trimester of pregnancy, and a high rate of fetal wastage occurs (> 85% fetal mortality) (CDC , 2000; Price et al, 1988; Monson et al, 1987; Walls, 1985). In the pregnant patient, especially in the third trimester, an improved maternal outcome is likely to be due to termination of the pregnancy-associated immunosuppression and to elimination of the heavy placental viral load (Nzerue, 1992; Price et al, 1988). Spontaneous abortion is common (DC Pigott , 2001; McCormick et al, 1987). Infection in the first trimester of pregnancy is associated with lower mortality compared to later in pregnancy (McCormick, 1988; Price et al, 1988).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) No specific studies are needed for most patients. Tests should be directed towards a patient's symptoms.
    B) Monitor fluid and serum electrolytes in patients with significant vomiting and/or diarrhea; intravascular volume loss may be significant.
    C) Monitor vital signs and mental status as indicated. Monitor for evidence of encephalopathy and seizures.
    D) Nonspecific laboratory abnormalities include proteinuria and elevated liver enzymes, with AST levels exceeding those of ALT. The combination of proteinuria, fever, pharyngitis, and chest pain appears to be a good diagnostic predictor of Lassa fever in endemic areas.
    E) Monitor CBC with differential and platelet count.
    F) Definitive diagnosis of Lassa fever can be made by isolating the virus from blood, urine or throat washings and then demonstrating the presence of immunoglobulin M (IgM) antibody to Lassa virus or showing a 4-fold rise in titer of IgG antibody between acute- and convalescent-phase serum specimens. In the early stages of the disease, reverse transcription-polymerase chain reaction (RT-PCR) can be performed. In a high containment laboratory, the Lassa virus can be cultured in 7 to 10 days. A postmortem diagnosis can be made using immunohistochemistry which is performed on formalin-fixed tissue specimens.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Laboratory findings are nonspecific and variable. Obtain CBC, electrolytes, blood cultures, CSF, and/or liver function tests as indicated. Mild hyperbilirubinemia and elevated liver enzymes are common. Nonspecific laboratory abnormalities include elevated liver enzymes, with aspartate aminotransferase (AST) levels exceeding those of alanine aminotransferase (ALT). Adverse prognostic factors are AST elevation above 150 IU/L and high viremia during hospitalization (Johnson et al, 1987; McCormick et al, 1987; McCormick, 1986).
    a) A CBC may NOT reveal leukopenia or thrombocytopenia, which are rare in Lassa fever. Neutrophilia is common (DC Pigott , 2001; Nzerue, 1992; Knobloch et al, 1980).
    2) Monitor fluid and electrolyte status in all symptomatic patients; vomiting and diarrhea are common; intravascular volume loss may be significant.
    3) BUN and serum creatinine may be elevated due to dehydration (McCormick et al, 1987).
    B) COAGULATION STUDIES
    1) Prothrombin, partial thromboplastin, international normalized ratio, and clotting times may rarely be prolonged in cases of Lassa fever (DC Pigott , 2001; McCormick, 1988; Fisher-Hoch et al, 1988).
    a) In 5 hemorrhagic Lassa fever cases, partial thromboplastin time, prothrombin time, and fibrin degradation products were tested and all were within normal range (Knobloch et al, 1980).
    2) A disseminated intravascular coagulation profile (fibrinogen level, fibrin degradation products) may be useful (DC Pigott , 2001); however, evidence of disseminated intravascular coagulation is rare (McCormick et al, 1987).
    4.1.3) URINE
    A) URINALYSIS
    1) Monitor for proteinuria and granular casts in all symptomatic patients. Proteinuria is reported in approximately two-thirds of patients with Lassa fever (Nzerue, 1992).
    4.1.4) OTHER
    A) OTHER
    1) CULTURES
    a) Definitive diagnosis of Lassa fever can be made by isolating Lassa virus from blood, urine, or throat washings during the first week of illness. High viremia (greater than 10(3) TCID50/mL) is a poor prognostic factor (Nzerue, 1992). The virus can be cultured in 7 to 10 days. Due to risks associated with handling infectious materials, perform minimum necessary laboratory testing for diagnostic evaluation. Postmortem diagnosis can be made from immunohistochemistry performed on tissue specimens (CDC , 2000).
    1) Clinical specimens from potentially infected persons should be submitted to a Biosafety Level 4 containment facility (DC Pigott , 2001; (Anon, 2000); Anon, 1989).

Radiographic Studies

    A) CHEST RADIOGRAPH
    1) Monitor chest x-ray in symptomatic patients. ARDS may occur late in illness (Frame, 1992; Cummins, 1990).

Methods

    A) MULTIPLE ANALYTICAL METHODS
    1) Definitive diagnosis of Lassa fever can be made by isolating the virus from blood, urine or throat washings and then demonstrating the presence of immunoglobulin M (IgM) antibody to Lassa virus or showing a 4-fold rise in titer of IgG antibody between acute- and convalescent-phase serum specimens (Centers for Disease Control and Prevention, 2015; DC Pigott , 2001; Trappier et al, 1993; Nzerue, 1992; Holmes et al, 1990; Jahrling et al, 1985; Niklasson et al, 1984). In the early stages of the disease, reverse transcription-polymerase chain reaction (RT-PCR) can be performed. In a high containment laboratory, the Lassa virus can be cultured in 7 to 10 days. A postmortem diagnosis can be made using immunohistochemistry which is performed on formalin-fixed tissue specimens (Centers for Disease Control and Prevention, 2015; DC Pigott , 2001; Trappier et al, 1993; Nzerue, 1992; Holmes et al, 1990; Jahrling et al, 1985; Niklasson et al, 1984). Antibodies has also been measured with the indirect fluorescent antibody technique (IFA) (DC Pigott , 2001; Trappier et al, 1993; Nzerue, 1992; Holmes et al, 1990; Jahrling et al, 1985; Niklasson et al, 1984). A triple-antibody ELISA method has been shown to be sensitive for the detection, quantitation and rapid diagnosis of Lassa viral antigens and antibodies in serum (Niklasson et al, 1984).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.5) DISPOSITION/DERMAL EXPOSURE
    6.3.5.1) ADMISSION CRITERIA/DERMAL
    A) All patients with suspected Lassa fever should be admitted to a hospital for further observation, treatment, and isolation to prevent further spread.
    6.3.5.2) HOME CRITERIA/DERMAL
    A) All patients with suspected Lassa fever should be referred to a hospital for further observation, treatment, and isolation to prevent further spread. Close contacts of filovirus-infected patients should be stringently monitored and asked to report any fever (ie, record temperature twice daily for 3 weeks). Casual contacts with Lassa virus-infected patients should be placed on alert and asked to report any fever.
    6.3.5.3) CONSULT CRITERIA/DERMAL
    A) An infectious disease specialist should be consulted and involved in the care of all cases. Critically ill patients may require the support of an intensivist. All confirmed and suspected cases should be reported immediately through local and State health departments to the Viral Special Pathogens Branch of the Centers for Disease Control (CDC).
    6.3.5.5) OBSERVATION CRITERIA/DERMAL
    A) Any person who has a history of close physical contact with an infected patient(s) should be put under strict surveillance (ie, obtain temperature twice daily; in the case of a temperature greater than 38.3 degrees C (101 degrees F), hospitalize the patient immediately in strict isolation). Surveillance should be continued for 3 weeks after the date of the last contact. Hospital personnel who come in close contact with patients or contaminated material without barrier attire should be considered exposed and put under close, supervised surveillance. High risk contacts (unprotected contact with patient's body fluids or excretions) should receive prophylaxis with ribavirin therapy.

Monitoring

    A) No specific studies are needed for most patients. Tests should be directed towards a patient's symptoms.
    B) Monitor fluid and serum electrolytes in patients with significant vomiting and/or diarrhea; intravascular volume loss may be significant.
    C) Monitor vital signs and mental status as indicated. Monitor for evidence of encephalopathy and seizures.
    D) Nonspecific laboratory abnormalities include proteinuria and elevated liver enzymes, with AST levels exceeding those of ALT. The combination of proteinuria, fever, pharyngitis, and chest pain appears to be a good diagnostic predictor of Lassa fever in endemic areas.
    E) Monitor CBC with differential and platelet count.
    F) Definitive diagnosis of Lassa fever can be made by isolating the virus from blood, urine or throat washings and then demonstrating the presence of immunoglobulin M (IgM) antibody to Lassa virus or showing a 4-fold rise in titer of IgG antibody between acute- and convalescent-phase serum specimens. In the early stages of the disease, reverse transcription-polymerase chain reaction (RT-PCR) can be performed. In a high containment laboratory, the Lassa virus can be cultured in 7 to 10 days. A postmortem diagnosis can be made using immunohistochemistry which is performed on formalin-fixed tissue specimens.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) DECONTAMINATION
    1) Oral decontamination measures following exposure to Lassa virus has not been proven to be effective and are NOT recommended.
    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 Lassa 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 ((Anon, 2000)). 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 ((Anon, 2000); CDC, 1995; Fisher-Hoch et al, 1995; Fisher-Hoch et al, 1985).
    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 greater than 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) Treatment should include recommendations listed in the DERMAL EXPOSURE section when appropriate.
    B) Oral decontamination measures would not be expected to be effective in Lassa virus infectious processes. Irrigate oral mucous membranes copiously.
    6.5.3) TREATMENT
    A) SUPPORT
    1) Treatment should include recommendations listed in the DERMAL 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 Lassa virus infections should receive monitoring for development of systemic infection.
    6.8.2) TREATMENT
    A) GENERAL TREATMENT
    1) Treatment should include recommendations listed in the DERMAL EXPOSURE section when appropriate.
    B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Dermal Exposure

    6.9.2) TREATMENT
    A) SUPPORT
    1) SUMMARY
    a) MANAGEMENT OF MILD TO MODERATE TOXICITY: The mainstay of treatment is symptomatic and supportive care. Treat patients with Lassa fever with ribavirin. It has been shown to prevent death from Lassa fever when given at any stage in the disease. High risk contacts (unprotected contact with patient's body fluids or excretions) should receive prophylaxis with ribavirin therapy. They should also record their temperatures twice daily for 3 weeks postexposure. If they develop a fever (greater than 101 degrees F) or other systemic symptoms within 3 weeks of exposure, they should receive further medical evaluation.
    b) MANAGEMENT OF SEVERE TOXICITY: The mainstay of treatment is good supportive care. Patients may require aggressive treatment for sepsis, including fluids and pressors for hypotension and intubation and ventilation for respiratory symptoms. Management of shock can be difficult. Response to fluid infusions is often poor, and these patients can readily develop pulmonary edema. Seizures may be treated with benzodiazepines, barbiturates, and/or propofol.
    2) Isolation precautions against bloody discharges and airborne transmission should be observed. Strict barrier nursing techniques should be enforced to prevent secondary transmission (Fisher-Hoch et al, 1985).
    3) Ribavirin therapy may be effective; a controlled clinical trial has shown an increased survival rate for Lassa fever patients treated with this drug (McCormick, 1986).
    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.
    5) Lassa fever convalescent immune plasma has not been shown to be beneficial due to low neutralizing antibody titers and currently cannot be recommended (Franz et al, 1997; Nzerue, 1992; McCormick, 1986).
    B) MONITORING OF PATIENT
    1) No specific studies are needed for most patients. Tests should be directed towards a patient's symptoms.
    2) Monitor fluid and serum electrolytes in patients with significant vomiting and/or diarrhea; intravascular volume loss may be significant.
    3) Monitor vital signs and mental status as indicated. Monitor for evidence of encephalopathy and seizures.
    4) Nonspecific laboratory abnormalities include proteinuria and elevated liver enzymes, with AST levels exceeding those of ALT. The combination of proteinuria, fever, pharyngitis, and chest pain appears to be a good diagnostic predictor of Lassa fever in endemic areas.
    5) Monitor CBC with differential and platelet count.
    6) Definitive diagnosis of Lassa fever can be made by isolating the virus from blood, urine or throat washings and then demonstrating the presence of immunoglobulin M (IgM) antibody to Lassa virus or showing a 4-fold rise in titer of IgG antibody between acute- and convalescent-phase serum specimens. In the early stages of the disease, reverse transcription-polymerase chain reaction (RT-PCR) can be performed. In a high containment laboratory, the Lassa virus can be cultured in 7 to 10 days. A postmortem diagnosis can be made using immunohistochemistry which is performed on formalin-fixed tissue specimens.
    C) RIBAVIRIN
    1) IV ribavirin has been found effective in the treatment of Lassa fever, but has not received US Food and Drug Administration (FDA) approval for this indication. The product is available for compassionate use purposes from the manufacturer using the FDA Investigational New Drug (IND) process for single patient IND for compassionate or emergency use. Requests should be initiated by the provider through FDA (301-443-1240), with simultaneous notification to Valeant: 800-548-5100, extension 5 (domestic telephone) or 949-461- 6971 (international telephone) (Rollin, 2012).
    2) Ribavirin has been shown to prevent death from Lassa fever when given at any stage in the disease (Nzerue, 1992). The ability of the drug to prevent fatality in Lassa fever 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; Fisher-Hoch & McCormick, 1987; McCormick, 1986; McCormick, 1986).
    3) DOSES
    a) 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).
    b) 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 equal to or less than 75 kg) for 10 days (Borio et al, 2002).
    c) 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).
    4) High risk contacts with exposure to the virus, should receive postexposure chemoprophylaxis (ribavirin 600 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). Receive further evaluation if fever (greater than 101 degrees F) or other systemic symptoms present within 3 weeks of exposure ((Anon, 2000)). Benefits versus risk should be assessed in pregnant patients due to demonstrated teratogenic effects in animal studies.
    5) PREGNANCY: Ribavirin is contraindicated in pregnancy due to a risk of human teratogenicity. However, the associated mortality of viral hemorrhagic fever is higher in pregnancy. Thus, the benefits probably outweigh any fetal risk of ribavirin therapy. Dosing is the same as for adults (See description above) (Borio et al, 2002).
    6) 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.
    D) HYPOTENSIVE EPISODE
    1) Management of shock can be difficult. Response to fluid infusions is often poor, and these patients can readily develop pulmonary edema (Franz et al, 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).
    E) 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).
    F) AIRWAY MANAGEMENT
    1) In cases of airway compromise, supportive measures including endotracheal intubation and mechanical ventilation may be necessary.
    G) 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).
    H) VACCINE
    1) No vaccine for human use is currently available; however, development of a Lassa virus vaccine is underway at CDC (DC Pigott , 2001). Vaccinia virus-expressed Lassa virus structural full-length glycoproteins appear to be most effective in inducing protective immunity following a lethal challenge with Lassa virus to primates. This has not been evaluated yet in humans (Fisher-Hoch et al, 2000).
    I) CORTICOSTEROID
    1) It has been suggested that sensorineural hearing loss due to Lassa fever is linked to the host's immune response and not to viremia. Steroids have been shown to reduce the immune response as well as subsequent inflammation and result in better hearing recovery (Liao et al, 1992; Cummins, 1990). However, there is no data showing the effect of systemic steroids on the clinical course of the viremia.
    J) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Range Of Toxicity

Summary

    A) TOXICITY: As few as 1 to 10 organisms are capable of causing infection. The overall case fatality rate is about 1% to 2%. Among those hospitalized with Lassa fever, the mortality rate is 15% to 20%. During an epidemic, mortality rate can reach 50% in hospitalized patients. Poor prognostic indicators include elevated AST (greater than 150 International Units/L) with high viremia.

Minimum Lethal Exposure

    A) SUMMARY
    1) As few as 1 to 10 aerosolized Lassa virus organisms are capable of causing infection in humans (CDC, 1999; Franz et al, 1997). This virus is 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). The virus has been shown to be stable in aerosol, especially at low humidity and may be used in terrorist attacks (Nzerue, 1992).
    2) The overall case fatality rate is about 1% to 2%. Among those hospitalized with Lassa fever, the mortality rate is 15% to 20%. During an epidemic, mortality rate can reach 50% in hospitalized patients (Centers for Disease Control and Prevention, 2015; CDC , 2000; McCormick et al, 1987; McCormick, 1987).
    3) Probability of death increases significantly with elevated levels of viremia measured on hospital admission or during course of illness. Odds ratio of death with a viremia greater than 10(3) TCID50/mL is 3.7. Odds ratio of death with the same level of viremia AND a serum AST greater than or equal to 150 International Units/liter is 21.5. Outcome of disease is highly associated with viremia, but not with development of antibody (Johnson et al, 1987).

Maximum Tolerated Exposure

    A) SUMMARY
    1) PROGNOSTIC FACTORS: High mortality (76%) is associated with serum aspartate aminotransferase levels greater than 150 International Units/liter on admission or viremia greater than 10(3) TCID50/mL. About 83% of patients not meeting these criteria have survived (Nzerue, 1992; McCormick, 1986).
    2) In endemic areas, approximately 80% of infections have been found to be mild or subclinical; the remaining 20% have a severe multisystem disease (CDC , 2000; Nzerue, 1992).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) CONCENTRATION LEVEL
    a) CASE REPORT - Post-mortem serum Lassa fever virus concentrations in a 43-year-old male were reported to be 10(8) plaque-forming units (pfu) per milliliter. Concentration of virus in a liver specimen was reported as >10(3) pfu per gram of tissue (Holmes et al, 1990).
    b) CASE SERIES - Odds ratio of death in 137 patients with viremia >10(3) TCID50/milliliter was calculated as 3.7; odds ratio of death with the same level of viremia AND a serum AST >/= 150 IU/liter was 21.5 (Johnson et al, 1987).

Pharmacology Toxicology

Toxicologic Mechanism

    A) Lassa virus is zoonotic. Its natural host is the multimammate rat Mastomys natalensis. The rats are infected throughout life and shed high levels of virus in their urine. Humans acquire the virus when virus shed in the rat urine leaks to man by direct routes and possibly through aerosol spread. Transfers of the virus occur between human beings while in close physical contact, such as within family units. The virus gains entry into the body via breaks in the mucous membrane (skin, mouth) or respiratory route (Nzerue, 1992; McCormick et al, 1987; McCormick, 1986; Buckley & Casals, 1978).
    B) In humans, Lassa virus induces an infection characterized by marked pantropism, viremia, and viruria. A direct viral pathogenic action is suggested in human disease. The reticuloendothelial system is the probable site of early viral replication. The immune response involves formation of IgM antibodies. Cell mediated immunity is thought to be critical to viral clearance. A macrophage response is reported to occur, however, lymphocytic infiltration is minimal (Nzerue, 1992; Buckley & Casals, 1978).
    1) Gross pathological changes include edema, congestion of the heart, lungs, kidneys, and intestines, pleurisy and ascites, and gastrointestinal hemorrhage. Histopathological changes include focal interstitial pneumonitis, myocarditis, focal tubular necrosis in the kidney, scattered and focal eosinophilic necrosis of hepatocytes, atrophy of Malpighian corpuscles in the spleen, and lymphocytic infiltration about splenic veins.
    2) Guinea pigs infected with Lassa virus have shown respiratory insufficiency with pulmonary edema, alveolar hyaline membranes, myocarditis, and focal calcification of myocardial fibers and hepatocytes. This was paralleled by high organ virus titers. In human fatalities, the virus has been isolated from virtually all tissues.
    3) Arenaviruses do not appear to multiply in invertebrate cell cultures (Buckley & Casals, 1978).
    C) Marked cellular dysfunction and hemorrhage in fatal cases of the disease are reported. Studies have suggested the presence of plasma factors that engender endothelial dysfunction, inhibit platelet aggregation and thromboxane generation leading to hemorrhage. Research has shown these inhibitors to inhibit super-oxide generation activated neutrophils. Tissue edema, a key pathophysiologic change in Lassa fever infection, is due to this endothelial dysfunction (Nzerue, 1992).
    D) SHOCK - Messenger ribonucleic acid (mRNA) evidence of multiple cytokine activation exists. It is suggested that these cytokines lead to shock and increased vascular permeability, basic pathophysiologic processes most often seen in viral hemorrhagic infection (DC Pigott , 2001).
    E) McCormick (1988) reported that features of terminal Lassa fever are likely due to biochemical disturbances of endothelial cells and platelet function; these are indirectly related to virus replication.
    F) DEAFNESS - It has been suggested that sensorineural hearing loss is linked to the host's immune response and not to the viremia. Thus, a virally-induced immune response mechanism may be responsible for idiopathic sensorineural deafness, and steroids have been shown to reduce the immune response as well as subsequent inflammation and result in better hearing recovery (Liao et al, 1992; Cummins, 1990). However, there is no data showing the effect of systemic steroids on the clinical course of the viremia.

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