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article-131243_81	Comprehensive Review of Bioterrorism -- Issues of Concern -- Investigations and Management	The diagnosis of R. rickettsiae infection depends on IgM and IgG serologic responses in the setting of clinical suspicion. Serology can be negative early in the course of the disease, and repeat tests may be warranted. Rickettsia can be cultured but is difficult and has a high BSL requirement due to exposure risk. PCR is an alternative means of diagnosis. The patient can have thrombocytopenia, hyponatremia, and CSF pleocytosis. Doxycycline is the antibiotic of choice for treatment, including in children. Defervescence usually occurs within three days of starting therapy, and treatment is usually continued for seven to ten days or at least three days following defervescence. Mortality rates may be as high as 20% to 30% without appropriate treatment. Prompt initiation of treatment on the grounds of clinical suspicion is recommended. [35]	Comprehensive Review of Bioterrorism -- Issues of Concern -- Investigations and Management. The diagnosis of R. rickettsiae infection depends on IgM and IgG serologic responses in the setting of clinical suspicion. Serology can be negative early in the course of the disease, and repeat tests may be warranted. Rickettsia can be cultured but is difficult and has a high BSL requirement due to exposure risk. PCR is an alternative means of diagnosis. The patient can have thrombocytopenia, hyponatremia, and CSF pleocytosis. Doxycycline is the antibiotic of choice for treatment, including in children. Defervescence usually occurs within three days of starting therapy, and treatment is usually continued for seven to ten days or at least three days following defervescence. Mortality rates may be as high as 20% to 30% without appropriate treatment. Prompt initiation of treatment on the grounds of clinical suspicion is recommended. [35]
article-131243_82	Comprehensive Review of Bioterrorism -- Issues of Concern -- Investigations and Management	In psittacosis, workup may show mild leukopenia during the acute phase of the disease, which can later progress to profound leukopenia. There may be anemia likely secondary to hemolysis. Liver transaminase, as well as gamma-glutamyl transpeptidase, may be variably elevated. There may also be raised inflammatory markers. A chest X-ray is abnormal in about 80% to 90% of patients who require hospitalization. Findings on the X-ray include unilateral or bilateral consolidation, miliary lesions, interstitial infiltrates, or nodular infiltrates. The CDC diagnostic criteria for psittacosis include any one of the following in the setting of clinical suspicion: isolation of C. psittaci from respiratory secretions, a four-fold increase in the serum antibody titers between in samples collected two weeks apart, a single IgM antibody titer of 1:16 or higher. The treatment regimen of choice for psittacosis is doxycycline 100 mg twice daily for 10 to 14 days. Alternative regimens including in pregnancy include macrolides such as azithromycin and erythromycin for seven days. Third-line agents include fluoroquinolones, but these are less effective than first and second-line agents. [36]	Comprehensive Review of Bioterrorism -- Issues of Concern -- Investigations and Management. In psittacosis, workup may show mild leukopenia during the acute phase of the disease, which can later progress to profound leukopenia. There may be anemia likely secondary to hemolysis. Liver transaminase, as well as gamma-glutamyl transpeptidase, may be variably elevated. There may also be raised inflammatory markers. A chest X-ray is abnormal in about 80% to 90% of patients who require hospitalization. Findings on the X-ray include unilateral or bilateral consolidation, miliary lesions, interstitial infiltrates, or nodular infiltrates. The CDC diagnostic criteria for psittacosis include any one of the following in the setting of clinical suspicion: isolation of C. psittaci from respiratory secretions, a four-fold increase in the serum antibody titers between in samples collected two weeks apart, a single IgM antibody titer of 1:16 or higher. The treatment regimen of choice for psittacosis is doxycycline 100 mg twice daily for 10 to 14 days. Alternative regimens including in pregnancy include macrolides such as azithromycin and erythromycin for seven days. Third-line agents include fluoroquinolones, but these are less effective than first and second-line agents. [36]
article-131243_83	Comprehensive Review of Bioterrorism -- Issues of Concern -- Importance in Bioterrorism	C. burnetii is a category B biological weapon as per the CDC. Even though it can be disseminated on a large scale, its relatively low mortality rates make it less dangerous than category A agents. However, it might still be more suitable as a biological weapon due to its widespread availability, environmental stability, and potential for aerosolized use. Aerosolised C. burnetii is extremely infectious, with a single bacterium being enough to produce disease. [31]	Comprehensive Review of Bioterrorism -- Issues of Concern -- Importance in Bioterrorism. C. burnetii is a category B biological weapon as per the CDC. Even though it can be disseminated on a large scale, its relatively low mortality rates make it less dangerous than category A agents. However, it might still be more suitable as a biological weapon due to its widespread availability, environmental stability, and potential for aerosolized use. Aerosolised C. burnetii is extremely infectious, with a single bacterium being enough to produce disease. [31]
article-131243_84	Comprehensive Review of Bioterrorism -- Issues of Concern -- Importance in Bioterrorism	Concerning other rickettsial organisms, the CDC classifies Rickettsia prowazekii, Rickettsia rickettsii, and Chlamydia psittaci as category B biological weapon agents as well . The minuscule infectious dose required (less than 10 bacteria) coupled with the ability of the organism to aerosolize efficiently and the resulting poor clinical outcomes in patients make them potential bioterror agents. [32]	Comprehensive Review of Bioterrorism -- Issues of Concern -- Importance in Bioterrorism. Concerning other rickettsial organisms, the CDC classifies Rickettsia prowazekii, Rickettsia rickettsii, and Chlamydia psittaci as category B biological weapon agents as well . The minuscule infectious dose required (less than 10 bacteria) coupled with the ability of the organism to aerosolize efficiently and the resulting poor clinical outcomes in patients make them potential bioterror agents. [32]
article-131243_85	Comprehensive Review of Bioterrorism -- Issues of Concern -- VIRAL	Variola Major (Smallpox) [37]	Comprehensive Review of Bioterrorism -- Issues of Concern -- VIRAL. Variola Major (Smallpox) [37]
article-131243_86	Comprehensive Review of Bioterrorism -- Issues of Concern -- VIRAL	Variola major is a DNA virus that belongs to the orthopoxviridae genus and the Poxviridae family, consisting of other poxviruses such as parapoxvirus, suipoxvirus, capripoxvirus, and molluscipoxvirus. Only variola and molluscum contagiosum are specific human viruses. However, the other orthopoxviruses, including vaccinia, monkeypox, and cowpox, can also cause significant illness in humans, but only variola major has human to human transmission. All orthopoxviruses are large, brick-shaped virions with a complex structure and a diameter of about 200 nm. The viruses replicate in the host cell cytoplasm by utilizing a DNA-dependent RNA polymerase. Symptoms and Signs [37]	Comprehensive Review of Bioterrorism -- Issues of Concern -- VIRAL. Variola major is a DNA virus that belongs to the orthopoxviridae genus and the Poxviridae family, consisting of other poxviruses such as parapoxvirus, suipoxvirus, capripoxvirus, and molluscipoxvirus. Only variola and molluscum contagiosum are specific human viruses. However, the other orthopoxviruses, including vaccinia, monkeypox, and cowpox, can also cause significant illness in humans, but only variola major has human to human transmission. All orthopoxviruses are large, brick-shaped virions with a complex structure and a diameter of about 200 nm. The viruses replicate in the host cell cytoplasm by utilizing a DNA-dependent RNA polymerase. Symptoms and Signs [37]
article-131243_87	Comprehensive Review of Bioterrorism -- Issues of Concern -- VIRAL	After transmission of variola, primary viral replication (primary viremia) occurs at the infection site. Secondary viremia happens around the eighth day after infection, which presents with sudden onset of a fever. After a 12 to 14 day incubation, there can be high-grade fever, malaise, and a headache. There can be an associated maculopapular rash on the oral mucosa, pharynx, and face, spreading to the trunk and limbs. The typical rash is centrifugal and is most prominently visible on the face, limbs, palms, and soles. Smallpox lesions appear over one to two days. Smallpox is infectious during the initial week of the rash. Patients become non-infectious once the scabs separate.	Comprehensive Review of Bioterrorism -- Issues of Concern -- VIRAL. After transmission of variola, primary viral replication (primary viremia) occurs at the infection site. Secondary viremia happens around the eighth day after infection, which presents with sudden onset of a fever. After a 12 to 14 day incubation, there can be high-grade fever, malaise, and a headache. There can be an associated maculopapular rash on the oral mucosa, pharynx, and face, spreading to the trunk and limbs. The typical rash is centrifugal and is most prominently visible on the face, limbs, palms, and soles. Smallpox lesions appear over one to two days. Smallpox is infectious during the initial week of the rash. Patients become non-infectious once the scabs separate.
article-131243_88	Comprehensive Review of Bioterrorism -- Issues of Concern -- VIRAL	In addition to the ordinary type, three other distinct forms exist. Hemorrhagic type is associated with skin petechiae and mucosal or conjunctival bleeding. The mortality rates associated with hemorrhagic type are high. The flat-type is associated with toxemia and slow onset of skin lesions. This type also has a high mortality rate. The modified type is seen in previously vaccinated patients where the skin lesions evolve rapidly and are variable. This type has a low mortality rate. Investigations and Management [37]	Comprehensive Review of Bioterrorism -- Issues of Concern -- VIRAL. In addition to the ordinary type, three other distinct forms exist. Hemorrhagic type is associated with skin petechiae and mucosal or conjunctival bleeding. The mortality rates associated with hemorrhagic type are high. The flat-type is associated with toxemia and slow onset of skin lesions. This type also has a high mortality rate. The modified type is seen in previously vaccinated patients where the skin lesions evolve rapidly and are variable. This type has a low mortality rate. Investigations and Management [37]
article-131243_89	Comprehensive Review of Bioterrorism -- Issues of Concern -- VIRAL	Smallpox may be clinically diagnosed, but lab confirmation is important during the initial stages of an outbreak. Pustular fluid or scabs from suspected patients should be collected by recently vaccinated personnel using personal protection equipment. The specimen must be collected in an evacuated tube, sealed with tape, and transported in a second water-tight container. The relevant health department labs must immediately be notified. Specimen examination must be performed only in a BSL-4 facility. Identification of the species-specific DNA sequences is the preferred investigation of choice. Electron microscopy, immunohistochemistry, PCR, and serology are also useful. The definitive diagnosis and species identification are based on viral culture and subsequent characterization by PCR.	Comprehensive Review of Bioterrorism -- Issues of Concern -- VIRAL. Smallpox may be clinically diagnosed, but lab confirmation is important during the initial stages of an outbreak. Pustular fluid or scabs from suspected patients should be collected by recently vaccinated personnel using personal protection equipment. The specimen must be collected in an evacuated tube, sealed with tape, and transported in a second water-tight container. The relevant health department labs must immediately be notified. Specimen examination must be performed only in a BSL-4 facility. Identification of the species-specific DNA sequences is the preferred investigation of choice. Electron microscopy, immunohistochemistry, PCR, and serology are also useful. The definitive diagnosis and species identification are based on viral culture and subsequent characterization by PCR.
article-131243_90	Comprehensive Review of Bioterrorism -- Issues of Concern -- VIRAL	Before 1972, routine vaccination against smallpox was common in the United States and Europe. This was stopped following the completed eradication of the disease. Protective immunity from vaccination has never been evaluated satisfactorily. Hence, the present population globally is considered immunologically naive and unprotected against smallpox if the disease is reintroduced. The CDC and the WHO maintain a small stockpile of conventional vaccines. There are recent efforts to produce a newer vaccine based on live cell culture. Since only very few doses of the vaccine exist, an Advisory Committee on Immunization Practices in 2001 recommended that preventive vaccination be started in first-line responders, including emergency and other first-line health care and law enforcement personnel, with a booster dose every 10 years. However, at present, widespread vaccination is administered only in case of an epidemic that can potentially occur due to a lab error or deliberate acts of bioterrorism.	Comprehensive Review of Bioterrorism -- Issues of Concern -- VIRAL. Before 1972, routine vaccination against smallpox was common in the United States and Europe. This was stopped following the completed eradication of the disease. Protective immunity from vaccination has never been evaluated satisfactorily. Hence, the present population globally is considered immunologically naive and unprotected against smallpox if the disease is reintroduced. The CDC and the WHO maintain a small stockpile of conventional vaccines. There are recent efforts to produce a newer vaccine based on live cell culture. Since only very few doses of the vaccine exist, an Advisory Committee on Immunization Practices in 2001 recommended that preventive vaccination be started in first-line responders, including emergency and other first-line health care and law enforcement personnel, with a booster dose every 10 years. However, at present, widespread vaccination is administered only in case of an epidemic that can potentially occur due to a lab error or deliberate acts of bioterrorism.
article-131243_91	Comprehensive Review of Bioterrorism -- Issues of Concern -- VIRAL	No antiviral drugs have been found to be effective against human smallpox infections. Hence, surveillance and containment, which was the strategy used in smallpox eradication in the past, are the strategies currently in place in the event of an outbreak. Contact tracing involving the identification and surveillance of the patients’ contacts are the cornerstones of these techniques. Administration of vaccines within four days of exposure is considered to be effective in preventing smallpox. Vaccinated contacts do not transmit the disease and do not require isolation. Environmental decontamination after a bioterrorist attack using aerosolized smallpox is paramount to control the spread. Importance in Bioterrorism [37]	Comprehensive Review of Bioterrorism -- Issues of Concern -- VIRAL. No antiviral drugs have been found to be effective against human smallpox infections. Hence, surveillance and containment, which was the strategy used in smallpox eradication in the past, are the strategies currently in place in the event of an outbreak. Contact tracing involving the identification and surveillance of the patients’ contacts are the cornerstones of these techniques. Administration of vaccines within four days of exposure is considered to be effective in preventing smallpox. Vaccinated contacts do not transmit the disease and do not require isolation. Environmental decontamination after a bioterrorist attack using aerosolized smallpox is paramount to control the spread. Importance in Bioterrorism [37]
article-131243_92	Comprehensive Review of Bioterrorism -- Issues of Concern -- VIRAL	Even though smallpox was eradicated completely in 1980, it is still a potentially dangerous bioweapon. The CDC categorizes it as a category A organism due to its ability to easily transmit from human to human. Smallpox has a high mortality rate with the potential to cause panic and subsequent social disruption in the event of a bioterrorist attack. The release of aerosolized smallpox is a looming threat, with numerous models developed for emergency response. Viral Hemorrhagic Fevers [38]	Comprehensive Review of Bioterrorism -- Issues of Concern -- VIRAL. Even though smallpox was eradicated completely in 1980, it is still a potentially dangerous bioweapon. The CDC categorizes it as a category A organism due to its ability to easily transmit from human to human. Smallpox has a high mortality rate with the potential to cause panic and subsequent social disruption in the event of a bioterrorist attack. The release of aerosolized smallpox is a looming threat, with numerous models developed for emergency response. Viral Hemorrhagic Fevers [38]
article-131243_93	Comprehensive Review of Bioterrorism -- Issues of Concern -- VIRAL	Viral hemorrhagic fevers include a group of severe illnesses characterized by bleeding manifestations of varying degrees, caused by four virus families, including Arenaviridae, Bunyaviridae, Filoviridae, and Flaviviridae. The Arenaviridae family includes: Chapare virus (CHPV), which causes Chapare hemorrhagic fever Guanarito virus (GTOV), which causes Venezuelan hemorrhagic fever Junin virus (JUNV) causes Argentine hemorrhagic fever Lassa virus (LASV), which causes Lassa fever Lujo virus (LUJV), which causes Lujo hemorrhagic fever Lymphocytic choriomeningitis virus (LCMV) which causes Lymphocytic choriomeningitis Machupo virus (MACV) which causes Bolivian hemorrhagic fever Sabia virus (SABV) causes Brazilian hemorrhagic fever	Comprehensive Review of Bioterrorism -- Issues of Concern -- VIRAL. Viral hemorrhagic fevers include a group of severe illnesses characterized by bleeding manifestations of varying degrees, caused by four virus families, including Arenaviridae, Bunyaviridae, Filoviridae, and Flaviviridae. The Arenaviridae family includes: Chapare virus (CHPV), which causes Chapare hemorrhagic fever Guanarito virus (GTOV), which causes Venezuelan hemorrhagic fever Junin virus (JUNV) causes Argentine hemorrhagic fever Lassa virus (LASV), which causes Lassa fever Lujo virus (LUJV), which causes Lujo hemorrhagic fever Lymphocytic choriomeningitis virus (LCMV) which causes Lymphocytic choriomeningitis Machupo virus (MACV) which causes Bolivian hemorrhagic fever Sabia virus (SABV) causes Brazilian hemorrhagic fever
article-131243_94	Comprehensive Review of Bioterrorism -- Issues of Concern -- VIRAL	The Bunyaviridae family includes: Crimean-Congo hemorrhagic virus (CCHFV), which causes Crimean-Congo hemorrhagic fever Dobrava-Belgrade virus (DOBV), which causes hemorrhagic fever with renal syndrome Hantaan virus (HTNV), which causes hemorrhagic fever with renal syndrome Puumalavirus (PUUV), which causes hemorrhagic fever with renal syndrome Rift Valley fever virus (RVFV), which causes Rift Valley fever Saaremaa virus (SAAV), which causes Hemorrhagic fever with renal syndrome Seoul virus (SEOV), which causes hemorrhagic fever with renal syndrome Sin Nombre virus (SNV), which causes Hantavirus pulmonary syndrome Severe fever and thrombocytopenia syndrome virus (SFTSV), which causes severe fever, and thrombocytopenia syndrome Tula virus (TULV), which causes hemorrhagic fever with renal syndrome	Comprehensive Review of Bioterrorism -- Issues of Concern -- VIRAL. The Bunyaviridae family includes: Crimean-Congo hemorrhagic virus (CCHFV), which causes Crimean-Congo hemorrhagic fever Dobrava-Belgrade virus (DOBV), which causes hemorrhagic fever with renal syndrome Hantaan virus (HTNV), which causes hemorrhagic fever with renal syndrome Puumalavirus (PUUV), which causes hemorrhagic fever with renal syndrome Rift Valley fever virus (RVFV), which causes Rift Valley fever Saaremaa virus (SAAV), which causes Hemorrhagic fever with renal syndrome Seoul virus (SEOV), which causes hemorrhagic fever with renal syndrome Sin Nombre virus (SNV), which causes Hantavirus pulmonary syndrome Severe fever and thrombocytopenia syndrome virus (SFTSV), which causes severe fever, and thrombocytopenia syndrome Tula virus (TULV), which causes hemorrhagic fever with renal syndrome
article-131243_95	Comprehensive Review of Bioterrorism -- Issues of Concern -- VIRAL	The Filoviridae family includes: Bundibugyo ebolavirus (BDBV), which causes Ebola virus disease Marburg marburgvirus (MARV), which causes Marburg hemorrhagic fever Sudan ebolavirus (SUDV), which causes Ebola virus disease Tai Forest ebolavirus (TAFV), which causes Ebola virus disease Zaire ebolavirus (EBOV), which causes Ebola virus disease The Flaviviridae family includes: Dengue virus (DENV-1-4), which causes Dengue fever Kyasanur forest disease virus (KFDV), which causes Kyasanur forest disease Omsk hemorrhagic fever virus (OHFV), which causes Omsk hemorrhagic fever Yellow fever virus (YFV), which causes Yellow fever	Comprehensive Review of Bioterrorism -- Issues of Concern -- VIRAL. The Filoviridae family includes: Bundibugyo ebolavirus (BDBV), which causes Ebola virus disease Marburg marburgvirus (MARV), which causes Marburg hemorrhagic fever Sudan ebolavirus (SUDV), which causes Ebola virus disease Tai Forest ebolavirus (TAFV), which causes Ebola virus disease Zaire ebolavirus (EBOV), which causes Ebola virus disease The Flaviviridae family includes: Dengue virus (DENV-1-4), which causes Dengue fever Kyasanur forest disease virus (KFDV), which causes Kyasanur forest disease Omsk hemorrhagic fever virus (OHFV), which causes Omsk hemorrhagic fever Yellow fever virus (YFV), which causes Yellow fever
article-131243_96	Comprehensive Review of Bioterrorism -- Issues of Concern -- VIRAL	Arenaviridae is associated with rodent vectors and is sub-divided into two groups: the New World and Old World groups. Infection can occur via direct contact with rodent droppings or urine or via aerosol transmission. There can be human-to-human as well as nosocomial infections with high mortality rates. For instance, the Lassa virus has a case fatality rate as high as 50%.	Comprehensive Review of Bioterrorism -- Issues of Concern -- VIRAL. Arenaviridae is associated with rodent vectors and is sub-divided into two groups: the New World and Old World groups. Infection can occur via direct contact with rodent droppings or urine or via aerosol transmission. There can be human-to-human as well as nosocomial infections with high mortality rates. For instance, the Lassa virus has a case fatality rate as high as 50%.
article-131243_97	Comprehensive Review of Bioterrorism -- Issues of Concern -- VIRAL	Bunyaviruses are associated with arthropods and rodents. These viruses can present with mild to moderate illness or severe illness with high mortality. For instance, in Crimean-Congo hemorrhagic fever, human-to-human transmission can occur through exposure to blood and bodily fluids with subsequent high mortality.	Comprehensive Review of Bioterrorism -- Issues of Concern -- VIRAL. Bunyaviruses are associated with arthropods and rodents. These viruses can present with mild to moderate illness or severe illness with high mortality. For instance, in Crimean-Congo hemorrhagic fever, human-to-human transmission can occur through exposure to blood and bodily fluids with subsequent high mortality.
article-131243_98	Comprehensive Review of Bioterrorism -- Issues of Concern -- VIRAL	Filoviruses can cause Ebola and Marburg hemorrhagic fever and are associated with African bats. Human to human transmission is reported with extremely high case fatality rates. Ebola outbreaks tend to have case fatality rates of more than 80% to 90%. Case fatality rates in Marburg hemorrhagic fever have been reported to be around 82% in a previous outbreak.	Comprehensive Review of Bioterrorism -- Issues of Concern -- VIRAL. Filoviruses can cause Ebola and Marburg hemorrhagic fever and are associated with African bats. Human to human transmission is reported with extremely high case fatality rates. Ebola outbreaks tend to have case fatality rates of more than 80% to 90%. Case fatality rates in Marburg hemorrhagic fever have been reported to be around 82% in a previous outbreak.
article-131243_99	Comprehensive Review of Bioterrorism -- Issues of Concern -- VIRAL	Flaviviruses are transmitted by arthropods and include the Dengue virus, which is transmitted by the Aedes aegypti mosquito. Dengue fever has a relatively low mortality rate of around 0.8% to 2.5%, but this can increase in more severe forms of the disease, namely dengue hemorrhagic fever. Symptoms and Signs [38]	Comprehensive Review of Bioterrorism -- Issues of Concern -- VIRAL. Flaviviruses are transmitted by arthropods and include the Dengue virus, which is transmitted by the Aedes aegypti mosquito. Dengue fever has a relatively low mortality rate of around 0.8% to 2.5%, but this can increase in more severe forms of the disease, namely dengue hemorrhagic fever. Symptoms and Signs [38]
article-131243_100	Comprehensive Review of Bioterrorism -- Issues of Concern -- VIRAL	Patients with viral hemorrhagic fevers can present with very non-specific symptoms, including fever, headache, and malaise. Common clinical features across the different viral hemorrhagic fevers include arthralgia, retro-orbital pain, eye redness, vomiting, abdominal pain, and diarrhea. There may also be hemorrhagic manifestations, including bleeding gums, epistaxis, petechiae, and other major bleeding episodes.	Comprehensive Review of Bioterrorism -- Issues of Concern -- VIRAL. Patients with viral hemorrhagic fevers can present with very non-specific symptoms, including fever, headache, and malaise. Common clinical features across the different viral hemorrhagic fevers include arthralgia, retro-orbital pain, eye redness, vomiting, abdominal pain, and diarrhea. There may also be hemorrhagic manifestations, including bleeding gums, epistaxis, petechiae, and other major bleeding episodes.
article-131243_101	Comprehensive Review of Bioterrorism -- Issues of Concern -- Investigations and Management	The lab tests in viral hemorrhagic fevers should include complete and differential blood counts, blood type and cross, coagulation studies, liver function tests, kidney function tests, chest x-ray, urinalysis, urine culture, and blood cultures to rule out other more common differentials. [38] Leukopenia, thrombocytopenia, and transaminitis are commonly encountered. [39] Serological testing for the specific IgM and IgG is useful, but molecular-based testing, including PCR, is the most sensitive test. Virus isolation by cell culture may also be used in diagnostic testing. [38]	Comprehensive Review of Bioterrorism -- Issues of Concern -- Investigations and Management. The lab tests in viral hemorrhagic fevers should include complete and differential blood counts, blood type and cross, coagulation studies, liver function tests, kidney function tests, chest x-ray, urinalysis, urine culture, and blood cultures to rule out other more common differentials. [38] Leukopenia, thrombocytopenia, and transaminitis are commonly encountered. [39] Serological testing for the specific IgM and IgG is useful, but molecular-based testing, including PCR, is the most sensitive test. Virus isolation by cell culture may also be used in diagnostic testing. [38]
article-131243_102	Comprehensive Review of Bioterrorism -- Issues of Concern -- Investigations and Management	Management of viral hemorrhagic fevers relies on early diagnosis to increase the chances of survival and prevent secondary bacterial infections. For a large number of viral hemorrhagic fevers, patients should be isolated with the treating staff using personal protective equipment except in certain viruses such as Dengue. The cornerstone of currently available treatment options is supportive care. A few examples of specific infections include: the Lassa virus and ribavirin improve treatment outcomes when administered early in the course of the infection. In Crimean-Congo hemorrhagic fever, treatment is supportive care. In Ebola virus disease and Marburg hemorrhagic fever, the treatment again involves supportive care. However, there is currently an approved Ebola vaccine against Ebola Zaire. There are no effective antiviral agents available in dengue fever, and management is based on supportive care. A vaccine is currently available in South America and South-East Asia. [38]	Comprehensive Review of Bioterrorism -- Issues of Concern -- Investigations and Management. Management of viral hemorrhagic fevers relies on early diagnosis to increase the chances of survival and prevent secondary bacterial infections. For a large number of viral hemorrhagic fevers, patients should be isolated with the treating staff using personal protective equipment except in certain viruses such as Dengue. The cornerstone of currently available treatment options is supportive care. A few examples of specific infections include: the Lassa virus and ribavirin improve treatment outcomes when administered early in the course of the infection. In Crimean-Congo hemorrhagic fever, treatment is supportive care. In Ebola virus disease and Marburg hemorrhagic fever, the treatment again involves supportive care. However, there is currently an approved Ebola vaccine against Ebola Zaire. There are no effective antiviral agents available in dengue fever, and management is based on supportive care. A vaccine is currently available in South America and South-East Asia. [38]
article-131243_103	Comprehensive Review of Bioterrorism -- Issues of Concern -- Investigations and Management	Importance in Bioterrorism [40]	Comprehensive Review of Bioterrorism -- Issues of Concern -- Investigations and Management. Importance in Bioterrorism [40]
article-131243_104	Comprehensive Review of Bioterrorism -- Issues of Concern -- Investigations and Management	Viral hemorrhagic fevers are considered category A bioweapons by the CDC. These viruses are potential candidates as biological weapons as they are stable when aerosolized, can cause severe disease, and are difficult to treat. The Soviet Union and other countries have performed research regarding their use in warfare in the past.	Comprehensive Review of Bioterrorism -- Issues of Concern -- Investigations and Management. Viral hemorrhagic fevers are considered category A bioweapons by the CDC. These viruses are potential candidates as biological weapons as they are stable when aerosolized, can cause severe disease, and are difficult to treat. The Soviet Union and other countries have performed research regarding their use in warfare in the past.
article-131243_105	Comprehensive Review of Bioterrorism -- Issues of Concern -- Viral Encephalitis	A number of viruses that can cause encephalitis are considered potential bioweapons. These include tick-borne encephalitis virus (TBEV), Japanese encephalitis, West Nile virus, and Nipah virus.	Comprehensive Review of Bioterrorism -- Issues of Concern -- Viral Encephalitis. A number of viruses that can cause encephalitis are considered potential bioweapons. These include tick-borne encephalitis virus (TBEV), Japanese encephalitis, West Nile virus, and Nipah virus.
article-131243_106	Comprehensive Review of Bioterrorism -- Issues of Concern -- Viral Encephalitis	The tick-borne encephalitis virus (TBEV) is a spherical and lipid-enveloped RNA virus that belongs to the genus of Flavivirus in the Flaviviridae family. Humans usually contract the disease by the bite of an infected tick. Following the bite, the virus replicates locally. Dendritic skin cells serve as the site for viral replication followed by transport to regional lymph nodes. The virus disseminates into the spleen, liver, and bone marrow from the nodes, where it continues to replicate. Following this, TBEV infects the central nervous system and produces typical clinical manifestations. [41] Japanese encephalitis is the most common naturally occurring cause of viral encephalitis, and it is caused by a flavivirus and is transmitted by Culex mosquitos. The West Nile virus is a single-stranded, enveloped RNA virus that belongs to the Flaviviridae family. In natural infections, Culex mosquitos are the most common vector. [42]	Comprehensive Review of Bioterrorism -- Issues of Concern -- Viral Encephalitis. The tick-borne encephalitis virus (TBEV) is a spherical and lipid-enveloped RNA virus that belongs to the genus of Flavivirus in the Flaviviridae family. Humans usually contract the disease by the bite of an infected tick. Following the bite, the virus replicates locally. Dendritic skin cells serve as the site for viral replication followed by transport to regional lymph nodes. The virus disseminates into the spleen, liver, and bone marrow from the nodes, where it continues to replicate. Following this, TBEV infects the central nervous system and produces typical clinical manifestations. [41] Japanese encephalitis is the most common naturally occurring cause of viral encephalitis, and it is caused by a flavivirus and is transmitted by Culex mosquitos. The West Nile virus is a single-stranded, enveloped RNA virus that belongs to the Flaviviridae family. In natural infections, Culex mosquitos are the most common vector. [42]
article-131243_107	Comprehensive Review of Bioterrorism -- Issues of Concern -- Viral Encephalitis	Nipah virus is an RNA virus that belongs to the Paramyxoviridae family and Henipavirus genus. Nipah virus is a BSL 4 category pathogen and is featured on the WHO's priority list of organisms that are likely to cause outbreaks. [43]	Comprehensive Review of Bioterrorism -- Issues of Concern -- Viral Encephalitis. Nipah virus is an RNA virus that belongs to the Paramyxoviridae family and Henipavirus genus. Nipah virus is a BSL 4 category pathogen and is featured on the WHO's priority list of organisms that are likely to cause outbreaks. [43]
article-131243_108	Comprehensive Review of Bioterrorism -- Issues of Concern -- Symptoms and Signs	In TBEV, between 70% to 98% of infections are asymptomatic. The incubation period of TBEV infections ranges from two to 28 days. The illness may take on a monophasic or biphasic clinical picture. Patients with monophasic courses usually have central nervous system involvement in the form of meningitis or meningoencephalitis. A small number of patients present with a febrile illness and headache but do not develop meningitis which is termed the abortive form. The first phase correlates with the viremia and manifests as fever, headache, myalgia, arthralgia, malaise, anorexia, nausea, etc., which lasts for two to seven days, followed by an asymptomatic interval for about one week. The second phase presents as meningitis in approximately 50% of patients, meningoencephalitis in about 40%, and meningoencephalomyelitis in about 10% of cases. [41]	Comprehensive Review of Bioterrorism -- Issues of Concern -- Symptoms and Signs. In TBEV, between 70% to 98% of infections are asymptomatic. The incubation period of TBEV infections ranges from two to 28 days. The illness may take on a monophasic or biphasic clinical picture. Patients with monophasic courses usually have central nervous system involvement in the form of meningitis or meningoencephalitis. A small number of patients present with a febrile illness and headache but do not develop meningitis which is termed the abortive form. The first phase correlates with the viremia and manifests as fever, headache, myalgia, arthralgia, malaise, anorexia, nausea, etc., which lasts for two to seven days, followed by an asymptomatic interval for about one week. The second phase presents as meningitis in approximately 50% of patients, meningoencephalitis in about 40%, and meningoencephalomyelitis in about 10% of cases. [41]
article-131243_109	Comprehensive Review of Bioterrorism -- Issues of Concern -- Symptoms and Signs	In Japanese encephalitis, the incubation period ranges between four to 15 days. A prodrome of non-specific symptoms, including fever, headache, vomiting, diarrhea, and myalgia, is common. Encephalitis develops following this, presenting as altered mental status, confusion, and overt psychosis. Meningism and seizures may develop. Rarely mutism and flaccid paralysis can occur. In the later course of the illness, patients can develop dystonia and choreo-athetoid movements. [44]	Comprehensive Review of Bioterrorism -- Issues of Concern -- Symptoms and Signs. In Japanese encephalitis, the incubation period ranges between four to 15 days. A prodrome of non-specific symptoms, including fever, headache, vomiting, diarrhea, and myalgia, is common. Encephalitis develops following this, presenting as altered mental status, confusion, and overt psychosis. Meningism and seizures may develop. Rarely mutism and flaccid paralysis can occur. In the later course of the illness, patients can develop dystonia and choreo-athetoid movements. [44]
article-131243_110	Comprehensive Review of Bioterrorism -- Issues of Concern -- Symptoms and Signs	In West Nile virus infections, the incubation period varies from four days to two weeks. Symptoms include fever, myalgia, malaise, headache, vomiting, anorexia, and a maculopapular rash on the trunk. In some cases, there may be encephalitis or meningitis and other neurologic presentations, including seizures, muscle weakness, altered mental status, or flaccid paralysis. West Nile infection can also cause myelitis, resulting in a polio-like presentation. In West Nile infections involving the nervous system, mortality is high. [42] [45]	Comprehensive Review of Bioterrorism -- Issues of Concern -- Symptoms and Signs. In West Nile virus infections, the incubation period varies from four days to two weeks. Symptoms include fever, myalgia, malaise, headache, vomiting, anorexia, and a maculopapular rash on the trunk. In some cases, there may be encephalitis or meningitis and other neurologic presentations, including seizures, muscle weakness, altered mental status, or flaccid paralysis. West Nile infection can also cause myelitis, resulting in a polio-like presentation. In West Nile infections involving the nervous system, mortality is high. [42] [45]
article-131243_111	Comprehensive Review of Bioterrorism -- Issues of Concern -- Symptoms and Signs	Nipah virus has an incubation period ranging from four to 21 days. It can cause distinct syndromes in the form of acute encephalitis or respiratory illness, or a combination of both, depending on the strain. The mortality rate, too, varies with the strain but is generally high. Some patients may remain asymptomatic or may have a sub-clinical course. The symptomatic disease begins with prodromal symptoms, including fever, headache, and myalgia. Encephalitis can develop within a week, presenting with altered mental status, hypotonia, areflexia, myoclonus, gaze palsy, weakness, and a myriad of other neurological symptoms and signs. Rapid deterioration into a coma and subsequent mortality are reported in some outbreaks. In about 20% of survivors, the patients may have residual neurological deficits. Nipah virus infections also may relapse or present with late-onset encephalitis. The respiratory presentation can present with cough, breathing difficulties, and atypical pneumonia. [43]	Comprehensive Review of Bioterrorism -- Issues of Concern -- Symptoms and Signs. Nipah virus has an incubation period ranging from four to 21 days. It can cause distinct syndromes in the form of acute encephalitis or respiratory illness, or a combination of both, depending on the strain. The mortality rate, too, varies with the strain but is generally high. Some patients may remain asymptomatic or may have a sub-clinical course. The symptomatic disease begins with prodromal symptoms, including fever, headache, and myalgia. Encephalitis can develop within a week, presenting with altered mental status, hypotonia, areflexia, myoclonus, gaze palsy, weakness, and a myriad of other neurological symptoms and signs. Rapid deterioration into a coma and subsequent mortality are reported in some outbreaks. In about 20% of survivors, the patients may have residual neurological deficits. Nipah virus infections also may relapse or present with late-onset encephalitis. The respiratory presentation can present with cough, breathing difficulties, and atypical pneumonia. [43]
article-131243_112	Comprehensive Review of Bioterrorism -- Issues of Concern -- Investigations and Management	A case of TBEV infection is diagnosed by the following criteria: symptoms or signs of meningitis or meningoencephalitis, an elevated CSF cell count, and microbiologic evidence by the identification of specific IgM and IgG. Other than the specific criteria, ESR and CRP may be normal or elevated. Detection of viral RNA by RT-PCR in blood or CSF is limited to the initial phase of the illness, following which it may become negative. TBEV serum IgM antibodies can remain detectable for many months following acute infection, and TBEV IgG antibodies persist lifelong and prevent symptomatic reinfection. No specific antiviral treatment exists for the treatment of TBEV infections. Supportive care remains the mainstay of treatment. Dexamethasone is found to be useful in the reduction of cerebral edema in acute encephalitis. Two vaccines are approved for use in Europe. [41]	Comprehensive Review of Bioterrorism -- Issues of Concern -- Investigations and Management. A case of TBEV infection is diagnosed by the following criteria: symptoms or signs of meningitis or meningoencephalitis, an elevated CSF cell count, and microbiologic evidence by the identification of specific IgM and IgG. Other than the specific criteria, ESR and CRP may be normal or elevated. Detection of viral RNA by RT-PCR in blood or CSF is limited to the initial phase of the illness, following which it may become negative. TBEV serum IgM antibodies can remain detectable for many months following acute infection, and TBEV IgG antibodies persist lifelong and prevent symptomatic reinfection. No specific antiviral treatment exists for the treatment of TBEV infections. Supportive care remains the mainstay of treatment. Dexamethasone is found to be useful in the reduction of cerebral edema in acute encephalitis. Two vaccines are approved for use in Europe. [41]
article-131243_113	Comprehensive Review of Bioterrorism -- Issues of Concern -- Investigations and Management	In Japanese encephalitis, workup may show leukocytosis or hyponatremia. MRI or CT can show bilateral thalamic lesions or hemorrhage. ACSF study may show significant opening pressure elevation, increased protein, and normal glucose. Japanese encephalitis virus-specific serum or CSF IgM using ELISA is the most useful test. There are no effective antiviral agents licensed for Japanese encephalitis. The cornerstone of management is supportive care. Anti-convulsants are useful for seizure control. In around 30% to 50% of survivors, there may be residual neurological deficits and psychiatric symptoms post-recovery of the acute illness. An effective vaccine in a short-course regimen is currently available against Japanese encephalitis. The CDC recommends the vaccine in people traveling to endemic areas for a long period and travelers to a place with a known outbreak. [44]	Comprehensive Review of Bioterrorism -- Issues of Concern -- Investigations and Management. In Japanese encephalitis, workup may show leukocytosis or hyponatremia. MRI or CT can show bilateral thalamic lesions or hemorrhage. ACSF study may show significant opening pressure elevation, increased protein, and normal glucose. Japanese encephalitis virus-specific serum or CSF IgM using ELISA is the most useful test. There are no effective antiviral agents licensed for Japanese encephalitis. The cornerstone of management is supportive care. Anti-convulsants are useful for seizure control. In around 30% to 50% of survivors, there may be residual neurological deficits and psychiatric symptoms post-recovery of the acute illness. An effective vaccine in a short-course regimen is currently available against Japanese encephalitis. The CDC recommends the vaccine in people traveling to endemic areas for a long period and travelers to a place with a known outbreak. [44]
article-131243_114	Comprehensive Review of Bioterrorism -- Issues of Concern -- Investigations and Management	In West Nile virus infections, labs can reveal non-specific leukocytosis and raised inflammatory markers. Hyponatremia is common if the nervous system is involved. The definitive diagnosis depends on detecting West Nile virus serology using ELISA for the IgM in serum or CSF samples. A CSF study is usually typical of a viral meningitis picture with elevated protein, lymphocytes, and normal glucose levels. CT brain may not show any features in acute disease, but MRI may be useful to detect CNS involvement after several weeks. Treatment of West Nile virus infection is supportive care. Mild cases may be managed symptomatically with an excellent prognosis. Cases with CNS involvement will usually require rehabilitation with physical and occupational therapy. Some patients have persistent neurological defects, including cognitive, gross, and fine motor abnormalities, even after recovery from the infection. [42]	Comprehensive Review of Bioterrorism -- Issues of Concern -- Investigations and Management. In West Nile virus infections, labs can reveal non-specific leukocytosis and raised inflammatory markers. Hyponatremia is common if the nervous system is involved. The definitive diagnosis depends on detecting West Nile virus serology using ELISA for the IgM in serum or CSF samples. A CSF study is usually typical of a viral meningitis picture with elevated protein, lymphocytes, and normal glucose levels. CT brain may not show any features in acute disease, but MRI may be useful to detect CNS involvement after several weeks. Treatment of West Nile virus infection is supportive care. Mild cases may be managed symptomatically with an excellent prognosis. Cases with CNS involvement will usually require rehabilitation with physical and occupational therapy. Some patients have persistent neurological defects, including cognitive, gross, and fine motor abnormalities, even after recovery from the infection. [42]
article-131243_115	Comprehensive Review of Bioterrorism -- Issues of Concern -- Investigations and Management	In Nipah virus infections, throat swabs, blood, urine, and CSF for PCR are the mainstay of diagnosis in a patient suspected of having the disease. These must be done only in a BSL 4 laboratory. Virus isolation using a Vero cell line followed by definitive identification of the virus using PCR is also useful for diagnosis. Still, it may be of limited utility in an outbreak scenario. Serum or CSF IgM by ELISA is also used for diagnosis but may be useful only relatively late in the course of the disease. The serum neutralization test is considered the gold standard but is time-consuming. The management of Nipah virus infection depends on good supportive care. Ribavirin has been reported to decrease mortality, but reports are conflicting. Neutralizing human monoclonal antibodies is approved in an outbreak setting in India based on reports of efficacy. [43] The virus is highly infectious, with human-to-human transmission occurring through the respiratory route and body fluids, thereby necessitating isolation of the patients and strict contact tracing. [46]	Comprehensive Review of Bioterrorism -- Issues of Concern -- Investigations and Management. In Nipah virus infections, throat swabs, blood, urine, and CSF for PCR are the mainstay of diagnosis in a patient suspected of having the disease. These must be done only in a BSL 4 laboratory. Virus isolation using a Vero cell line followed by definitive identification of the virus using PCR is also useful for diagnosis. Still, it may be of limited utility in an outbreak scenario. Serum or CSF IgM by ELISA is also used for diagnosis but may be useful only relatively late in the course of the disease. The serum neutralization test is considered the gold standard but is time-consuming. The management of Nipah virus infection depends on good supportive care. Ribavirin has been reported to decrease mortality, but reports are conflicting. Neutralizing human monoclonal antibodies is approved in an outbreak setting in India based on reports of efficacy. [43] The virus is highly infectious, with human-to-human transmission occurring through the respiratory route and body fluids, thereby necessitating isolation of the patients and strict contact tracing. [46]
article-131243_116	Comprehensive Review of Bioterrorism -- Issues of Concern -- Importance in Bioterrorism	Tickborne encephalitis viruses are category C biological weapons as per the CDC. They are emerging viruses that can potentially be engineered for mass dissemination and have the potential for high morbidity and mortality. [47] Japanese encephalitis and West Nile virus are potentially transmissible by aerosolization, which makes them a potential bioweapon. [45]	Comprehensive Review of Bioterrorism -- Issues of Concern -- Importance in Bioterrorism. Tickborne encephalitis viruses are category C biological weapons as per the CDC. They are emerging viruses that can potentially be engineered for mass dissemination and have the potential for high morbidity and mortality. [47] Japanese encephalitis and West Nile virus are potentially transmissible by aerosolization, which makes them a potential bioweapon. [45]
article-131243_117	Comprehensive Review of Bioterrorism -- Issues of Concern -- Importance in Bioterrorism	Due to its high mortality rates, the respiratory route of human to human transmission, and its potential to be weaponized as an aerosol, the Nipah virus is considered a Category C priority organism by the CDC. Prasad et al. developed a lethal model using the Bangladesh strain of the Nipah virus and infected African green monkeys through aerosol exposure and demonstrated a lethality suggesting that the Nipah virus has a high potential for weaponization. [48]	Comprehensive Review of Bioterrorism -- Issues of Concern -- Importance in Bioterrorism. Due to its high mortality rates, the respiratory route of human to human transmission, and its potential to be weaponized as an aerosol, the Nipah virus is considered a Category C priority organism by the CDC. Prasad et al. developed a lethal model using the Bangladesh strain of the Nipah virus and infected African green monkeys through aerosol exposure and demonstrated a lethality suggesting that the Nipah virus has a high potential for weaponization. [48]
article-131243_118	Comprehensive Review of Bioterrorism -- Issues of Concern -- Coccidiodes immitis (coccidioidomycosis) and Histoplasma capsulatum (histoplasmosis)	Coccidioides are dimorphic fungi that can exist as mycelia or as spherules. It is endemic in certain states in the United States. In naturally occurring infections, the infectious particles of Coccidioides called arthroconidia are inhaled into the lung by the patient causing coccidioidomycosis or San Joaquin Valley fever. [49] Histoplasma capsulatum is a soil-dwelling dimorphic fungus present in pockets worldwide and is endemic in certain states of the United States. [50]	Comprehensive Review of Bioterrorism -- Issues of Concern -- Coccidiodes immitis (coccidioidomycosis) and Histoplasma capsulatum (histoplasmosis). Coccidioides are dimorphic fungi that can exist as mycelia or as spherules. It is endemic in certain states in the United States. In naturally occurring infections, the infectious particles of Coccidioides called arthroconidia are inhaled into the lung by the patient causing coccidioidomycosis or San Joaquin Valley fever. [49] Histoplasma capsulatum is a soil-dwelling dimorphic fungus present in pockets worldwide and is endemic in certain states of the United States. [50]
article-131243_119	Comprehensive Review of Bioterrorism -- Issues of Concern -- Symptoms and Signs	In coccidioidomycosis, around 60% of cases are asymptomatic. The incubation period can range between seven to 21 days. The symptoms include fever, cough, breathlessness, and chest pain. Headache, loss of weight, and a rash in the form of a faint maculopapular rash, erythema nodosum, or erythema multiforme may be seen. The combination of fever, erythema nodosum, and arthralgia is called desert rheumatism. Other than the common pulmonary presentation in the form of pneumonia, the patient may present with signs of pulmonary cavities, meningitis, abscesses, or disseminated infection involving multiple systems. [49]	Comprehensive Review of Bioterrorism -- Issues of Concern -- Symptoms and Signs. In coccidioidomycosis, around 60% of cases are asymptomatic. The incubation period can range between seven to 21 days. The symptoms include fever, cough, breathlessness, and chest pain. Headache, loss of weight, and a rash in the form of a faint maculopapular rash, erythema nodosum, or erythema multiforme may be seen. The combination of fever, erythema nodosum, and arthralgia is called desert rheumatism. Other than the common pulmonary presentation in the form of pneumonia, the patient may present with signs of pulmonary cavities, meningitis, abscesses, or disseminated infection involving multiple systems. [49]
article-131243_120	Comprehensive Review of Bioterrorism -- Issues of Concern -- Symptoms and Signs	In histoplasmosis, primary infections may be asymptomatic or may present with mild flu-like symptoms. The incubation period ranges between seven to 21 days. Symptoms in acute histoplasmosis include fever, headache, cough, and chest pain. The symptoms usually resolve in 10 days. Arthralgias, erythema nodosum, or erythema multiforme can develop in a small proportion of patients, but this is less common in histoplasmosis than coccidioidomycosis. Some patients may present as chronic pulmonary histoplasmosis in the form of cavitary or non-cavitary illness. In others, there may be disseminated histoplasmosis with uncontrolled growth and proliferation of the fungus in multiple organs, and the patient presents with fever, weight loss, hepatomegaly, and splenomegaly. [50]	Comprehensive Review of Bioterrorism -- Issues of Concern -- Symptoms and Signs. In histoplasmosis, primary infections may be asymptomatic or may present with mild flu-like symptoms. The incubation period ranges between seven to 21 days. Symptoms in acute histoplasmosis include fever, headache, cough, and chest pain. The symptoms usually resolve in 10 days. Arthralgias, erythema nodosum, or erythema multiforme can develop in a small proportion of patients, but this is less common in histoplasmosis than coccidioidomycosis. Some patients may present as chronic pulmonary histoplasmosis in the form of cavitary or non-cavitary illness. In others, there may be disseminated histoplasmosis with uncontrolled growth and proliferation of the fungus in multiple organs, and the patient presents with fever, weight loss, hepatomegaly, and splenomegaly. [50]