Viral hemorrhagic fevers (VHFs) are globally widespread and caused by viruses found within several different families. VHFs are considered category A bioterror agents, are zoonotic in origin, and unfortunately not all transmission vectors and/or reservoirs have been identified. Incubation period from exposure to development of symptoms may be up to 21 days, with an average of 5 to 14 days. Symptoms are initially nonspecific and may include acute onset of fever, cephalalgia, myalgias, gastrointestinal symptoms, and rash. Depending on the specific pathogen there may be unique features, but nevertheless the initial stage is often referred to as the dry stage. As disease progresses, patients may develop “wet” symptoms including massive fluid losses (can be up to and beyond 10 L/day) from diarrhea or emesis, hemorrhage from multiple sites, shock, and multiorgan dysfunction syndrome (MODS). In this phase, death is common, and mortality rates depending on the specific infection can range from 20% to 100%. ^, The classic hemorrhagic symptoms may not always be present but may often be subtle including ecchymoses at multiple sites, petechiae, conjunctival hemorrhages. The disease course itself can last up to 4 weeks or longer, and several hemorrhagic fever viruses have been shown to persist in immunosenescent areas of the body (ocular tissues, gonads) for years (filoviruses in particular).

Targeted medical countermeasures against most VHFs are limited. Effective vaccines exist for one species of Ebolavirus, and there are several promising candidates for other pathogens. Similarly, monoclonal antibody therapy cocktails are approved for Zaire Ebolavirus and are in clinical trials for other hemorrhagic fevers—these latter may be obtained via investigational new drug mechanisms via US federal pathways ( Table 1 ). Diagnosis is usually by reverse transcription-polymerase chain reaction (RT-PCR) syndromic testing at specialized laboratories, as these pathogens require rigorous biosafety level 4 precautions. Additionally, enzyme-linked immunoassays, viral culture, and immunohistochemistry may be performed, but their utility in acute outbreaks may be limited. With respect to treatment, only measure that has been consistently shown to improve mortality in these patients is early, optimized supportive critical care that includes management of potential bacterial and parasitic coinfections (ie, bacterial sepsis and malaria). Mortality has been shown to increase by 11%/day from symptom onset to initiation of early supportive care. Proper identification of these patients through symptom and travel screening, along with appropriate infection prevention and control measures, are essential to protecting patients, health care workers, and hospital systems. ^, Dengue, which can cause a hemorrhagic fever in its severe form, will be discussed later.

Anthrax is arguably the most likely bioterrorist or biological weapons scenario to occur and it has been successfully deployed in such a manner. In the wake of the events on September 11, 2001 in the United States, spores of Bacillus anthracis were sent, in an act of bioterrorism, through the mail resulting in 22 cases of anthrax, 5 of which were fatal. Anthrax is caused by B anthracis , a gram-positive spore-forming bacillus. There are 4 potential types of infection in humans depending on the route of exposure: cutaneous, inhalational, gastrointestinal, and injectional. The cutaneous form is the most common and least lethal, beginning as a pruritic papule evolving to a vesicle and then to a painless coal-black eschar associated with edema and lymphadenopathy. It can occasionally disseminate.

The inhalational form is most lethal and the form that would follow an intentional aerosol release resulting in a critically ill patient. The incubation period of inhalational anthrax can vary from 1 day to 6 weeks, with the onset of illness consisting of nonspecific symptoms characteristic of influenza-like illnesses, but importantly without rhinorrhea. Rapid progression to severe respiratory distress and shock occurs with evident hemorrhagic mediastinitis (identified as mediastinal widening and pleural effusions on chest X-ray or computed-tomography [CT] scans). It is important to be aware that over 50% of cases will have neurologic involvement that can manifest as meningitis. ^, Laboratory confirmation can be performed via blood culture (70% sensitive) or via cerebrospinal fluid (CSF), pleural, and vesicular fluid. Biopsy and polymerase chain reaction (PCR) are sensitive but not widely available, and serology is not useful early in the course of illness. Systemic anthrax is a toxin-mediated disease and therapy should include antimicrobials with anti-toxin activity. Empiric therapy consists of combination antimicrobials including a fluoroquinolone plus linezolid plus meropenem (for potential central nervous system [CNS] involvement) and a fluoroquinolone plus linezolid or clindamycin if meningitis has been ruled out. Minimum therapy duration is 2 to 3 weeks along with adjunctive steroids if meningitis present. Additionally, adjunctive anti-toxin monoclonal and polyclonal antibody-based therapy exists as single dose administration, though supplies are limited and would need to be obtained in consultation with local and federal partners. ^, It is also critical to drain any fluid collections that may be present such as pleural, pericardial, and ascitic—such collections should be considered to be empyema-like—as it confers a clinical benefit. There is no person–person transmission, and standard infection prevention precautions are sufficient.

Smallpox is caused by variola virus, of which the most common clinical form is variola major. Highly transmissible via droplet or aerosols, smallpox has an overall mortality of approximately 30%. Classic features include high fevers and a disseminated centrifugal rash that displays a synchronized progression of macules, papules, vesicles, and pustules. The incubation period may be 10 to 14 days, and patients are considered contagious until all lesions have completely healed over. The differential diagnosis includes disseminated primary varicella, disseminated herpes simplex virus (HSV), and severe mpox. ^, Diagnosis may be made via serologic testing, culture of lesions, PCR, and electron microscopy, though clinical suspicion remains essential. While the mainstay of treatment is supportive, proper infection prevention and control measures (including airborne and contact isolation, and potentially high-level containment) are essential. Close contacts need to be closely surveilled and quarantined. Several approved therapeutic medical countermeasures exist, including tecovirimat and brincidofovir, as well as vaccinia immune globulin. ^,, Additionally, two effective vaccines, one nonreplicating and one live, are approved for use. In recent years, another orthopox virus caused disease, mpox has emerged worldwide and is an important condition to also consider given the clinical similarity in the presentation (albeit with a lower mortality rate).

Plague is caused by Yersinia pestis , an aerobic gram-negative bacillus, and is a zoonotic infection of domestic and wild animals of which humans are incidental hosts. However, it can spread human-to-human through inhalation of contaminated aerosols and is highly contagious. Primary pneumonic plague has an incubation period of 1 to 3 days after inhalation or droplet transmission from another infected person, while secondary pneumonic plague develops in approximately 10% of patients as a result of hematogenous spread from bubonic or septicemic forms. The disease is characterized by the sudden onset of dyspnea, high fever, pleuritic chest pain, and hemoptysis leading to respiratory failure and shock. Diagnosis is often clinical but confirmed by culture; while rapid antigen tests exist in some endemic regions, none are approved for use in the United States—though the Western United States is a plague-endemic area in which approximately a dozen cases per year are reported. Appropriate and early antimicrobial therapy is essential and recommended with gentamicin, a fluoroquinolone, or doxycycline. For severe disease combination therapy is recommended for 14 days. Pneumonic plague is fatal unless antimicrobial therapy is begun within the first day of illness. ^,

Colloquially known as rabbit fever, tularemia is caused by the gram-negative coccobacillus known as Francisella tularensis . Several forms exist (pneumonic, typhoidal, ulceroglandular, and oculoglandular), and natural transmission of tularemia can occur through infected mosquitos, ticks, or rabbits. In summer months in the northern hemisphere this illness is sometimes diagnosed in landscapers, construction workers, and groundskeepers. An intentional release would likely cause pneumonic tularemia, with a mortality rate of 2% to 24%. With an incubation period of 3 to 5 days, symptoms resemble severe community-acquired pneumonia that can rapidly progress to septic shock, acute respiratory distress syndrome and respiratory collapse. Diagnosis requires enriched culture media, serology, immunofluorescence testing, or PCR, though laboratory personnel must be alerted to the potential pathogen to ensure proper biosafety precautions. Treatment is with an aminoglycoside, a fluoroquinolone, or doxycycline. Standard precautions are adequate as there is no human-to-human transmission.

Caused by the deadliest toxin known to humankind, botulism is caused by toxin release from the gram-positive spore forming Clostridium botulinum. There are 8 known toxin types (zinc endopeptidases) and by binding selectively and irreversibly to proteins at the presynaptic membrane the toxins prevent release of acetylcholine, causing flaccid paralysis. The 6 most common presentations include: infantile, wound, gastrointestinal, iatrogenic, inhalational, and foodborne. The main challenge with botulism is that the toxin is colorless and odorless when in gaseous form as would be anticipated from an intentional release. Six hours post-exposure to aerosolized botulinum toxin, a symmetric descending paralysis occurs with cranial nerve dysfunction (that may include diplopia, dysphagia, pupillary dilation, and ptosis) and progression to rapid respiratory failure. Importantly, fever and altered mental status may be absent. Importantly, facial paralysis may obscure clinical distress and because patients may not be hypoxic until late stages of disease, any signs of respiratory compromise should prompt consideration of inhalational botulism and early intubation. In fact, the intubation rate is approximately 50%.

Diagnosis is largely clinical though confirmatory tests do exist, albeit with significant delays. Culture may take up to 3 weeks, mouse bioassays may detect the toxin within 48 hours, and PCR detection may occur. However, early optimized critical care is the mainstay of treatment coupled with antitoxin and if suspicion is present, administration of antitoxin is vital. Equine-derived heptavalent (toxin A–G) botulinum antitoxin is the primary medical countermeasure, obtained from the US Centers for Disease Control (CDC). In a deliberate attack, the human-derived bivalent antitoxin BabyBIG should not be administered as it can only counteract toxins A and B.

Arboviruses are viruses that spread to humans through arthropod vectors (such as mosquitoes and ticks). Some cause VHFs and others typically occur during warm weather when specific vectors are more active. Diseases with the potential to lead to critical illness include dengue fever, yellow fever, Oropouche virus, chikungunya, and various encephalitic infections such as eastern equine encephalitis or West Nile virus. Infected mosquitos, specifically Aedes aegypti , are the main vector for several of these viruses, and due to climate change and intercontinental travel, their range has significantly expanded. Direct human-to-human transmission does not occur. Travel and symptom screens are essential to guide testing and management.

Dengue, spread by Aedes mosquitoes and maintained naturally in a sylvatic cycle with nonhuman primates, continues to become endemic in more countries in the Northern and Western hemispheres. There are four major serotypes and three clinical syndromes as defined by the World Health Organization and Pan-American Health Organization: dengue without warning signs (fever, retro-orbital headache, severe bone pain ( break-bone fever ), myalgias, maculopapular rash, and nausea/vomiting); dengue with warning signs (sustained abdominal pain, persistent vomiting, edema, mucosal bleeding, lethargy, hypotension, hepatomegaly, and increasing hematocrit); and severe dengue (shock or respiratory distress, severe bleeding, and organ failure). More serious forms of infection may occur following initial resolution of fever, and hemorrhagic fever may include neurologic involvement. Severe dengue is a manifestation of antibody-enhanced infection in which antibodies generated during a prior infection with one serotype enhance infection by another. Values show leukopenia, thrombocytopenia, and elevated transaminases. Diagnosis can be made via serology or RT-PCR. Treatment for each form of dengue fever is supportive. Given gastrointestinal and hematologic effects, non-steroidal anti-inflammatory drugs (NSAIDs) are to be avoided; oral rehydration (if able) or with isotonic fluids is strongly encouraged, and systemic glucocorticoids are also to be avoided in patients with severe dengue, including patients with shock.

It is important to note that in the United States, Dengue is common in American Samoa, Puerto Rico, the US Virgin Islands, the Federated States of Micronesia, the Republic of Mashall Islands, and the Republic of Palau. Local transmission of dengue has occurred in Hawaii, Texas, New York and Florida—areas where the requisite mosquito is present. It is also important to note that, until recently as of this writing, there was a safe, and effective live-attenuated vaccine, Dengvaxia, that provided significant protection against the four serotypes of the virus but was limited in its use, for safety reasons, to those with serologic evidence of prior infection and above the age of 6. It remains available in over 100 countries but not in all regions where endemic, and due to declining demand will no longer be produced. Other vaccine candidates are in advanced stages of research and one, Qdenga, is licensed in many countries.