African horse sickness virus
Second, biological weapons are potentially inexpensive to produce. In 1969, a United Nations study considered the cost to a belligerent of producing mass (defined as 50%) casualties and found crude biological weapons to be far less costly than chemical, nuclear, or even conventional arms on a “casualties per square kilometer” basis.17
Third, unless terrorists announced the release of a biological agent, detection of a biological attack would be challenging. Aerosolized biological agents would likely be odorless, colorless, tasteless, and otherwise invisible (in contrast to chemical agents, which often have characteristic odors). Standoff detection systems have been developed and efforts to improve their capabilities are ongoing; these have been employed during certain high-profile public events. The current favored technology for standoff biological detection is ultraviolet laser-induced fluorescence LIDAR (light detection and ranging).18 The initial detection of a bioterrorist attack may not be dependent on the finding of delivery devices such as explosive devices, missiles, or even crop-dusting equipment. Nor would it likely involve environmental detection or meteorological perturbations. Rather, it more likely will involve the presentation (perhaps widely dispersed geographically) of patients with nonspecific symptoms to various practitioners, clinics, and emergency departments. This makes effective management particularly difficult, as treatment of diseases such as anthrax, plague, and botulism is most effective when begun early (when nonspecific symptoms predominate), ideally during the incubation period. By the time hallmark findings (hemorrhagic mediastinitis and related chest findings in the case of anthrax, hemoptysis in plague victims, neuromuscular symptoms of botulism) appear, treatment is of dubious benefit and prognosis often poor. Moreover, with easy access to jet travel, incubation periods ensure that perpetrators can safely depart for any foreign land before detection. Additionally, contagious biological agents (smallpox and pneumonic plague) can continue to propagate among successive generations of victims prior to discovery and diagnosis.
Finally, victims of a biological attack, more so than conventional or chemical casualties, can potentially overwhelm medical response capabilities. Botulism provides an instructive example. A survivable disease in isolated cases with early diagnosis and access to modern medical interventions (such as lengthy courses of mechanical ventilation and other intensive care modalities), the sudden requirement for hundreds or thousands of patients requiring ventilation in a given city would render a large botulism outbreak difficult to manage.
With these considerations in mind, it is clear that the spectrum of biological terrorism warrants a level of planning and preparedness at least as great as that devoted to conventional and chemical terrorism. In fact, it is precisely a lack of preparedness that might amplify the allure of biological weapons in the minds of some terrorists. Capitalizing on this lack of preparedness, a terrorist might simply threaten the release of a biological agent. Such a threat may suffice to influence policy-making and engender a massive commitment of resources. For example, many hundreds of anthrax threats have come to the attention of law-enforcement agencies over the past decade. With the notable exception of the anthrax mailings of October 2001, however, virtually all of these threats have been unfounded.19 Yet, even the most amateur hoax or innocent but unwarranted concern has resulted in a response expending hundreds of thousands of dollars.
For bioterrorism defense planning and preparedness purposes, it is necessary to be familiar with the specific agents that might be employed by terrorists. The agents developed and studied by the Cold War superpowers (Tables 32.1 and 32.2) provide a starting point for consideration. An examination of a terrorist’s potential motives permits further refinement of these lists. A World Health Organization (WHO) study20 showed that anthrax is somewhat unique in its ability to produce widespread mortality. This study considered a release of 50 kg of agent along a 2-km line upwind of a city of 500,000 inhabitants. In this scenario, 250,000 persons would contract the disease, and 100,000 would die. Thus, for a terrorist group interested in producing widespread lethality, anthrax would be an ideal choice of weapon (assuming it could be procured, weaponized, and delivered optimally). Smallpox, a disease not considered in the WHO study, could produce similar or even greater magnitude health effects. Smallpox and pneumonic plague (and, to a lesser degree, certain viral hemorrhagic fevers) are noteworthy in that they, in contrast to other agents already mentioned in this chapter, are contagious. Terrorists might thus leverage the results of an attack by weaponizing smallpox or plague, infecting a modest number of persons in a “first wave” and depending on contagion to assist the agent in propagating through a population, thereby overcoming some of the technical challenges of widespread aerosol delivery.
While certain assumptions and generalizations can be made in attempting to define and combat the terrorist threat, the motives and rationale of terrorists are sometimes unpredictable. Shigella, giardia, and even roundworms have been employed as “weapons” by terrorists, criminals, or other disgruntled individuals.21 Envisioning and preparing for all these scenarios in advance would have been impractical. Given this factor and the constraint of limited resources, it is most useful to focus on agents both most likely to be used and also to produce the most devastating consequences. In June 1999, U.S. public health experts met in Atlanta and used this rationale to develop a list18,22 of “critical biological agents for health preparedness” (Table 32.4). Agents in Category A are those that, if effectively dispersed, would be expected to have a high overall public health impact. Consequently, significant medical intervention would be required and intensive public health preparedness is needed. Such preparedness includes stockpiling of medications and supplies as well as improvements in disease surveillance and response capabilities of local, state, federal, and international health authorities. Category B agents present a somewhat lesser requirement for preparedness, while Category C agents require vigilance in order to guard against their future development as threat agents, but might otherwise be adequately managed within the framework of the existing public health infrastructure. Because they are of most concern, category A agents will be discussed in more detail; a concise guide to the treatment of (and prophylaxis against) diseases caused by these agents is provided in Table 32.5.
Critical Agents for Public Health Preparedness
| Category A | Category B | Category C |
|---|---|---|
| Variola virus | Coxiella burnetii | Emerging threat agents (e.g., Nipah virus, hantaviruses, pandemic influenza viruses) |
| Bacillus anthracis | Brucellae | |
| Yersinia pestis | Burkholderia mallei | |
| Botulinum toxin | Burkholderia pseudomallei | |
| Francisella tularensis | Alphaviruses | |
| Filoviruses & Arenaviruses | Rickettsia prowezekii | |
| Certain toxins (Ricin, SEB) | ||
| Chlamydia psittaci | ||
| Food safety threat agents (Salmonellae, E. coli O157:H7) | ||
| Water safety threat agents (e.g., Vibrio cholera) |
Category A: Agents with high public health impact requiring intensive public health preparedness and intervention; Category B: Agents with a somewhat lesser need for public health preparedness; Category C agents are emerging infections that may pose a threat in the future.
Recommended Therapy and Prophylaxis for Diseases caused by ‘Category A’ Biothreat Agents, 2015 Version
| Condition | Adults | Children |
|---|---|---|
| Anthrax, Inhalational, Therapy1 (patients who are clinically stable after 14 days can be switched to a single oral agent [ciprofloxacin or doxycycline] to complete a 60-day course2) | Ciprofloxacin 400 mg IV q12h OR Levofloxacin 500 mg IV/PO qd OR Doxycycline 100 mg IV q12h AND Clindamycin3 900mg IV q8h AND Penicillin G4 4 mil U IV q4h AND Consider: Raxibacumab 40 mg/kg IV | Ciprofloxacin 10-15 mg/kg IV q12h OR Levofloxacin 8 mg/kg PO q12h OR Doxycycline 2.2 mg/kg IV q12h AND Clindamycin3 10-15 mg/kg IV q8h AND Penicillin G4 400-600k U/kg/d IV q4h AND Consider: Raxibacumab (>50 kg: 40 mg/kg IV; 15–50 kg: 60 mg/kg IV; <15 kg: 80 mg/kg IV) |
| Anthrax, Inhalational, Post-Exposure Prophylaxis (60- day course2) | Ciprofloxacin 500 mg PO q12h OR Levofloxacin 500 mg PO qd OR Doxycycline 100 mg PO q12h | Ciprofloxacin 10-15 mg/kg PO q12h OR Levofloxacin 8 mg/kg PO q12h OR Doxycycline 2.2 mg/kg PO q12h |
| Anthrax, Cutaneous in setting of Terrorism, Therapy5 | Ciprofloxacin 500 mg PO q12h OR Levofloxacin 500 mg PO qd OR Doxycycline 100 mg PO q12h | Ciprofloxacin 10-15 mg/kg PO q12h OR Levofloxacin 8 mg/kg PO q12h OR Doxycycline 2.2 mg/kg PO q12h |
| Plague, Therapy | Gentamicin 5 mg/kg IV qd OR Doxycycline 100 mg IV q12h OR Ciprofloxacin 400 mg IV q12h OR Levofloxacin 500 mg IV/PO qd OR Moxifloxacin 400 mg PO/IV qd x10-14 days | Gentamicin 2.5 mg/kg IV q8h OR Doxycycline 2.2 mg/kg IV q12h OR Ciprofloxacin 15 mg/kg IV q12h OR Levofloxacin 8 mg/kg IV/PO q12h |
| Plague, Prophylaxis | Doxycycline 100 mg PO q12h OR Ciprofloxacin 500 mg PO q12h OR Levofloxacin 500 mg PO qd OR Moxifloxacin 400 mg PO/IV qd x10-14 days | Doxycycline 2.2 mg/kg PO q12h OR Ciprofloxacin 20 mg/kg PO q12h OR Levofloxacin 8 mg/kg PO q12h |
| Tularemia, Therapy & Prophylaxis | Same as for Plague6 | Same as for Plague6 |
| Smallpox, Therapy | Supportive Care | Supportive Care |
| Smallpox, Prophylaxis | Vaccination may be effective if given within the first several days after exposure. | Vaccination may be effective if given within the first several days after exposure. |
| Botulism, Therapy | Supportive Care; Antitoxin may halt the progression of symptoms but is unlikely to reverse them. | Supportive Care; Antitoxin may halt the progression of symptoms but is unlikely to reverse them. |
| Viral Hemorrhagic Fevers, Therapy | Supportive Care; Ribavirin may be beneficial in select cases. | Supportive Care; Ribavirin may be beneficial in select cases. |
1 In a mass casualty setting, where resources are constrained, oral therapy may need to be substituted for the preferred parenteral option.
2 If the organism is sensitive, children may be switched to oral amoxicillin (80 mg/kg/d q8h) to complete a 60-day course. Current recommendations, however, are that the first 14 days of therapy or post-exposure prophylaxis include ciprofloxacin, levofloxacin, or doxycycline regardless of age. A three-dose series of Anthrax Vaccine Adsorbed (AVA) may permit shortening of the antibiotic course to 30 days.
3 Rifampin or clarithromycin also target bacterial protein synthesis may thus be acceptable alternatives to clindamycin. If ciprofloxacin or another quinolone is employed, doxycycline may be used as a second agent, as it also targets protein synthesis.
4 Ampicillin, imipenem, meropenem, or chloramphenicol penetrate the CSF well and may thus be acceptable alternatives to penicillin.
5 Ten days of therapy may be adequate for endemic cutaneous disease. Current recommendations, however, recommend a full 60-day course in the setting of terrorism because of the possibility of a concomitant inhalational exposure.
6 Levofloxacin is licensed by the U.S. Food and Drug Administration for the prophylaxis and treatment of plague in the setting of a bioterror attack, but not tularemia.
7 On May 8, 2015, the Food and Drug Administration approved moxifloxacin for the prevention and treatment of plague in adults (http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm446283.htm (Accessed August 27, 2015)).
Category A Agents
Anthrax
The causative agent of anthrax, Bacillus anthracis, is a Gram-positive, sporulating, rod-shaped bacterium. Anthrax is primarily an endemic and epidemic disease of livestock. Ungulates such as sheep, goats, and cattle are exposed through the ingestion of soil-borne spores while grazing. These spores germinate within the animal, multiply rapidly in the bloodstream, and lead to death within days. At the time of death, the animal’s blood may contain as many as 108 bacterium per cubic centimeter; these bacteria, once exposed to oxygen as the animal decomposes, sporulate, enter the soil, and continue the cycle.
B. anthracis has several characteristics that make it a useful biological weapon: 1) it is easy to obtain – the organism can be found virtually anywhere in the world where livestock are kept but are not routinely immunized against anthrax; 2) it grows readily in easily-prepared media; 3) it can easily be induced to form spores, which are not only highly infective via the aerosol route, but can be stored for an extended time with minimal degradation; 4) spore size and durability facilitate highly efficient aerosol delivery as a biological weapon.
Human anthrax takes three primary forms – cutaneous, gastrointestinal, and inhalational. Cutaneous anthrax is the most common naturally occurring form of human disease. Approximately 7 days (range 1–12 days) following exposure to infected hides or meat, a painless or mildly pruritic papule forms at the site of exposure. The lesion rapidly enlarges and ulcerates, often developing vesicles or bullae at the margins, and often accompanied by significant surrounding edema and regional lymphadenopathy. As the ulcer dries, it forms a coal-black scab (hence the name, “anthrax,” from the Greek anthracis meaning coal) which resolves over 1–2 weeks (Figure 32.1). Up to 20% of untreated cutaneous anthrax cases progress to systemic disease and result in death. Notably, eleven of the twenty-two suspected or documented cases of anthrax from the 2001 “Amerithrax” mailings were cutaneous in nature.14 In addition, cutaneous, inhalational, and gastrointestinal anthrax have been reported since 2006 from exposure to imported African animal skins.23,24
Cutaneous Anthrax. Note the painless black eschar and moderate surrounding erythema.
Oropharyngeal anthrax is a variation of cutaneous anthrax in which ingestion of contaminated meat leads to an oropharyngeal lesion and associated neck edema and adenopathy; the mortality rate in oropharyngeal anthrax can be much higher than that for other forms of cutaneous anthrax, likely due to the increased incidence of systemic spread as well as airway compromise resulting from oropharyngeal edema.25
Gastrointestinal anthrax results from consumption of insufficiently cooked meat from infected animals. Between 1 and 6 days following ingestion, fever, nausea, vomiting, and focal abdominal pain ensue. Victims then typically develop massive gastrointestinal bleeding and sepsis, with a fatal outcome occurring in more than 50% of cases.25
Historically, inhalational anthrax has been an extraordinarily rare disease found only in wool or hide mill workers after exposure to high concentrations of anthrax spores that are aerosolized by manipulation of contaminated animal products. Disease is the result of inhalation of aerosolized spores, which are then ingested by alveolar macrophages and carried to mediastinal lymph nodes, where they multiply and release toxins. Typically 1–6 days after exposure (but possibly up to several months later) disease onset is heralded by a nonspecific febrile illness, often accompanied by malaise, fatigue, and drenching sweats. Pneumonia is rare, and an auscultatory exam of the lungs is often normal at this phase of the illness, although radiologic studies may demonstrate pleural effusions and the classic widened mediastinum of hemorrhagic mediastinitis. Upper respiratory symptoms such as rhinorrhea or nasal congestion are rare in inhalational anthrax. Cough, if present, is generally non-productive. If untreated, disease that has progressed this far will typically lead to severe respiratory distress, shock, and death within 2–5 days. Historically, mortality for inhalational anthrax was greater than 85%, although only five of the eleven victims with inhalational anthrax (45%) succumbed in the Amerithrax mailings of 2001. This improvement in outcome likely reflects the aggressive management of the recent cases with modern intensive care resources, but might also be skewed simply because of the small numbers. Patients with all forms of anthrax disease should be managed using standard infection control precautions. Person-to-person spread of anthrax is extremely rare, even in inhalational cases. Invasive procedures that can generate infectious aerosols should, however, be avoided in patients who may be bacteremic. In addition, it is at least theoretically possible for person-to-person transmission of cutaneous anthrax to occur via nonintact skin; therefore standard precautions should be followed for individuals with open skin or mucosal lesions.
Effective diagnosis of anthrax relies on a strong clinical suspicion to drive appropriate confirmatory laboratory studies. For systemic febrile disease resulting from any form of anthrax, blood cultures may be diagnostic if performed prior to antibiotic administration. For mild cutaneous disease, culture of the lesion (ideally vesicle fluid) may be positive; Gram stain of vesicle fluid may show large, Gram-positive bacilli; and immunohistochemical stains can identify anthrax in culture-negative lesions. In patients with gastrointestinal anthrax, stool cultures are sometimes positive; hemorrhagic peritoneal fluid can also be cultured or immunostained for B. anthracis. A widened mediastinum with or without pleural effusions on chest radiograph or computerized tomography suggests inhalational anthrax (Figure 32.2). Gram stain of pleural fluid or cerebrospinal fluid (in the presence of meningitis, seen in up to 50% of inhalational anthrax cases and hemorrhagic in character) is often positive, and specific immunostaining or polymerase chain reaction of these fluids can be diagnostic.25 Furthermore, newer treatment guidelines recommend that fluid drainage be performed on anthrax patients with ascites or pleural effusions. In the event of pericardial effusions, drainage should only be performed when hemodynamic compromise is present.26
(A) Chest X-ray demonstrates mediastinal and hilar widening and bilateral pleural effusions. (B) Chest computed tomography scan demonstrates enlarged, hyperdense subcarinal (arrow) and left hilar (arrowhead) lymph nodes probably secondary to intranodal hemorrhage. (C) Note the peribronchial consolidation, which reflects lymphatic spread of anthrax infection. Images courtesy of JR Garvin, MD, and AA Frazier, MD, Department of Radiologic Pathology, Armed Forces Institute of Pathology, Washington, DC.
The key clinical decision point for the treatment of anthrax is based on the presence or absence of meningitis (Figure 32.3). Meningitis is frequently present in inhalational anthrax cases, is often fatal, and an enhanced therapy of three drugs is recommended: one with a high central nervous system (CNS) penetration (e.g., meropenem), a protein synthesis inhibitor (e.g., linezolid), and a bactericidal agent (e.g., ciprofloxacin). In the absence of meningitis, the CNS penetrating agent can be omitted.26
Meningitis with subarachnoid hemorrhage in a man from Thailand who died 5 days after eating undercooked carabao (water buffalo). Reproduced from: Binford CH, Connor DH, eds. Pathology of Tropical and Extraordinary Diseases, Vol. 1. Washington, DC: Armed Forces Instituted of Pathology, 1976: 121. AFIP Negative 75-12374-3.
Uncomplicated cutaneous anthrax disease should be treated initially with either ciprofloxacin (500 mg PO bid for adults or 10–15 mg/kg/d divided bid [up to 1,000 mg/d] for children) or doxycycline (100 mg PO bid for adults, 5 mg/kg/d divided bid for children less than 8 years [up to 200 mg/d]). If the strain proves to be penicillin-susceptible, then the treatment may be switched to amoxicillin (500 mg PO tid for adults or 80 mg/kg PO divided tid [up to 1,500 mg/d] for children) (Table 32.5). Antitoxin antibody should also be administered to patients with systemic illness.26
While the B. anthracis genome encodes for beta-lactamases, the organism may still respond to penicillins (such as amoxicillin) if slowly growing, as in localized cutaneous disease. In the event that the exposure route is unknown or suspected to be intentional, antibiotics should be continued for at least 60 days. If the exposure is known to have been due to contact with infected livestock or their products, then 7–10 days of antibiotics may suffice. For patients with significant edema, non-steroidal anti-inflammatory drugs (NSAIDs) or corticosteroids may be of benefit. Debridement of lesions is not indicated. If systemic illness accompanies cutaneous anthrax, then intravenous (IV) antibiotics should be administered as per the inhalational anthrax recommendations discussed previously.27,28,29
While fluoroquinolone and tetracycline antibiotics are generally not recommended for use in children and pregnant women, a U.S. consensus group, as well as the American Academy of Pediatrics,30,31 recommended ciprofloxacin or doxycycline as first-line therapy in life-threatening anthrax disease or in disease suspected to be of sinister origin (because penicillin-resistant strains can readily be selected for in the laboratory) until strain susceptibilities are known. The U.S. Food and Drug Administration (FDA) approved ciprofloxacin for prophylaxis and treatment of anthrax in children; it is the first choice for antibiotics in pregnant women.27 If the infecting strain later proves to be penicillin-susceptible, transition to oral penicillin VK or amoxicillin is acceptable for cases of mild cutaneous anthrax.
For all forms of symptomatic anthrax aside from mild cutaneous disease (including inhalational, gastrointestinal, oropharyngeal, and severe cutaneous forms), combination IV antibiotics are strongly advised. Initial empiric therapy should include ciprofloxacin or doxycycline plus one or two additional antibiotics effective against anthrax. B. anthracis-susceptible antibiotics include: imipenem, meropenem, daptomycin, quinupristin-dalfopristin, linezolid, vancomycin, rifampin, the macrolides, clindamycin, chloramphenicol, and the aminoglycosides. Oral therapy should replace IV antibiotics when the patient’s clinical course dictates, although in most situations, the optimal duration of therapy and antibiotic combination is not known. A monoclonal antibody, raxibacumab, was approved in 2012 as an adjunct to antibiotics in the treatment of inhalational anthrax. Finally, human anthrax immune globulin, collected from recipients of Anthrax Vaccine Adsorbed (AVA),32,33 is a potential adjunctive therapy that is FDA-licensed.
AVA is a protein vaccine produced from the supernatant of a culture of an attenuated strain of B. anthracis. In the United States, it is licensed for the prevention of anthrax, and is provided to certain laboratory workers, selected first responders, and military personnel. It is administered subcutaneously in an initially five-dose series over 18 months (0 and 4 weeks; then 6, 12, and 18 months), followed by annual boosters. While AVA is only licensed for preexposure prophylaxis of anthrax in adults aged 18 to 65 years, it is available under Investigational New Drug (IND) protocol for preexposure use in children, and post-exposure prophylaxis in adults and children. Its safety and efficacy in post-exposure prophylaxis, however, has not been established.32,33 Patients with a history of hypersensitivity reactions to previous doses should not receive AVA; the vaccine should be deferred in pregnancy, persons with a febrile infectious disease, and those taking immunosuppressant drugs such as corticosteroids. FDA reports that AVA is “safe and effective” in preventing all forms of anthrax disease.32
Following an aerosolized attack with B. anthracis, exposed persons should receive antibiotic prophylaxis to prevent development of disease. Even previously immunized victims should immediately receive oral ciprofloxacin, levofloxacin, or doxycycline, all of which have been licensed for this application. Should the offending strain later be determined to be penicillin-sensitive, penicillin VK or amoxicillin can be substituted for those who cannot tolerate first-line antibiotics. Antibiotics should be continued for at least 60 days, as spores can remain dormant within a victim’s lungs for extended periods only to germinate later, after the victim has completed weeks of prophylaxis. After completing antibiotics, patients should receive close follow-up for development of fever or other signs and symptoms of anthrax infection.34
Smallpox
Smallpox is a disease limited to humans and caused by the Orthopox virus Variola major. A related strain, Variola minor, causes a milder form of disease termed alastrim. Historically, smallpox was a significant cause of human suffering and death worldwide, responsible for as many as 50 million cases per year in the 1950s. WHO declared smallpox to be eradicated in 1980 after a monumental worldwide vaccination campaign. However, significant concern remains that existing laboratory-based Variola virus isolates could be reintroduced as weapons into an increasingly susceptible population. Variola is easily grown in cell culture or chicken eggs, and is readily dried into a stabile form, which can survive prolonged storage and is suitable for aerosolization. Contagious via droplet nuclei, smallpox can spread readily through a susceptible population, with secondary attack rates as high as 50% in nonimmune household contacts.35
People typically acquired smallpox via mucous membrane contact with infectious respiratory droplet nuclei from an infected, coughing individual. Less commonly, disease was transmitted via direct contact with lesions or secretions, fomites, or via infectious aerosols. Approximately 12 days (range 7–19 days) after inoculation, an infected person experienced the sudden onset of high fever (38.8–40.0° C), malaise, headache, and shaking chills. The patient would often be bedridden with severe backache, abdominal pain, and vomiting. Within 2–3 days after symptom onset, the patient would experience mild improvement, with decreased fever, and develop an enanthem in the form of small, painful ulcerations of the tongue and oropharynx (Figure 32.4). Oral secretions at this phase of illness are teeming with Variola virus, and the patient is a significant infectious risk. Within a day of enanthem onset, 2–3-mm erythematous macules appear on the face and distal extremities. The macules progress to papules, and then to clear vesicles over the next 3–5 days, and finally to tense, painful, centrally umbilicated pustules shortly thereafter, often accompanied by a second fever spike. As the lesions evolve, they spread centrally, although they typically remain more pronounced and abundant on the face and distal extremities. Death, if it occurs, typically does so during this second week of infection. Among survivors, pustules further progress to scabs, which separate to leave depressed, hypopigmented, permanent scars that are often quite disfiguring.36 Scabs contain viable virus; the patient is thus considered contagious and requires strict isolation until scabs are entirely shed.
The evolution of skin lesions in an unvaccinated infant with the classic form of Variola major (A1, A2). The third day of rash shows synchronous eruption of skin lesions; some are becoming vesiculated (B1, B2). On the fifth day of rash, almost all papules are vesicular or pustular (C1, C2). On the seventh day of rash, many lesions demonstrate central umbilication, and all lesions are in the same general stage of development. Reproduced with permission from Fenner FHD, Arita I, Jezek Z, Ladnyi ID. Smallpox and its eradication. Geneva, World Health Organization, 1988.
The severity of smallpox disease in the past was quite variable, with several forms of disease described. Morbidity, and ultimate mortality, were directly related to the number and concentration of skin lesions; confluent lesions portended a particularly bad outcome. Disease was generally more severe in women (especially if pregnant), children, the elderly, certain ethnic groups (e.g., Native Americans and Pacific Islanders), and immunocompromised individuals. Partially immune individuals (i.e., vaccinated) tended to have mild disease, with few lesions and lower mortality – a syndrome closely resembling that seen in Variola minor. Flat-type smallpox (Figure 32.5) probably represented an extreme form of confluent smallpox in which the skin took on a uniform “crepe rubber” appearance instead of forming classic lesions; it was seen most commonly in children. Hemorrhagic smallpox (Figure 32.6) was a rare form of fulminant disease with associated bleeding diatheses seen predominantly during pregnancy and in immunocompromised individuals. Mortality from classic smallpox varied from 10–30% in nonimmune individuals, to roughly 3% in the immunized. Among pregnant women, the mortality rate was as high as 65%, and flat and hemorrhagic forms of disease were fatal in 95% of cases. Long-term complications of smallpox included blindness from corneal scarring (1–4% of cases),37 growth abnormalities in children secondary to Variola osteomyelitis (2–5% of child cases),38 and disfiguring or physically debilitating dermal scarring from the pox lesions themselves.
Flat-type smallpox in an unvaccinated woman on the sixth day of rash. Extensive flat lesions (A and B) and systemic toxicity with a fatal outcome were typical. Reproduced with permission from Fenner FHD, Arita I, Jezek Z, Ladnyi ID. Smallpox and its eradication. Geneva, World Health Organization, 1988.
Early hemorrhagic-type smallpox with cutaneous signs of hemorrhagic diathesis. Death usually intervened before the complete evolution of pox lesions.
Since routine immunization of U.S. civilians against smallpox ceased in 1972, there is an increase in the immunologically naive population. This coupled with the ease of global travel means that smallpox would likely spread faster than it did in the past. Historically, close person-to-person contact was required for transmission to occur reliably. Spread was greatest after exposure to persons with confluent rash or severe enanthem and to those with bronchiolitis and cough. While person-to-person contact is typically required, spread via aerosol is well-documented in hospital outbreaks.39 Thus Variola can also be spread by contact with contaminated bedding, especially in the hospital setting, although such factors typically played a small role in overall transmission through a population. In past outbreaks, environmental conditions are thought to have factored prominently in disease propagation. Smallpox spread more quickly in conditions of low humidity, and during winter or rainy seasons, when people would crowd together in their homes. The disease tended to spread slowly through partially immune communities, but could become endemic in densely populated regions, even in a population with up to 80% vaccination rates.35
Historically, the diagnosis of smallpox was largely based on characteristic clinical findings, particularly the rash. In some cases, such clinical diagnosis could be problematic. Prodromal smallpox is difficult to differentiate from other febrile syndromes. The early rash of smallpox has been commonly mistaken for varicella, and other viral exanthems (e.g., adenovirus), as well as conditions, such as erythema multiforme, that may cause febrile illness with rash. Flat type and hemorrhagic smallpox may be difficult to differentiate clinically from other fulminant infectious syndromes presenting with shock and disseminated intravascular coagulation.
Monkeypox, another Orthopox virus closely related to smallpox, occurs naturally in equatorial Africa. While monkeypox is not a Category A agent, it can be clinically indistinguishable from smallpox. The differences are a much lower case fatality rate (11% or less in non-immunized) and the presence of cervical and inguinal lymphadenopathy, appearing 1–2 days before the rash in 90% of cases.40 An outbreak involving eighty-one human cases of monkeypox occurred in 2003 in the United States due to exposure to exotic pets (such as Gambian rats) imported from West Africa. These cases demonstrated only localized lesions and mild disease, with no secondary transmission occurring among humans.41 Past data from Africa suggests that the smallpox vaccine is at least 85% effective in preventing monkeypox. It is recommended that the vaccine be given within 4 days from the date of exposure in order to prevent onset of the monkeypox. If given between 4 and 14 days after the date of exposure, vaccination may reduce the symptoms of the disease, but may not prevent the disease.42
There are no proven specific therapies for smallpox (Table 32.5). Parenteral cidofovir is an antiviral drug (licensed for use in cytomegalovirus retinopathy) that shows in-vitro activity against a broad range of poxviruses, and potential in-vivo benefit in animal studies of poxvirus infections. Additional studies are underway to determine whether parenteral or oral cidofovir might be efficacious in the treatment of human Orthopox virus infections.43 Patients with ocular smallpox may benefit from treatment with topical antivirals such as trifluridine or idoxuridine. Aggressive supportive care is the cornerstone of successful management of smallpox disease and includes maintenance of hydration and nutrition, pain control, and prevention and treatment of secondary infections.
Infection control within healthcare facilities could represent a significant challenge; smallpox patients should be isolated under contact and airborne precautions. Caregivers should be immunized and wear appropriate personal protective equipment (PPE), regardless of their immunization status. Providers who collect or process specimens should only do so under the direction of public health officials.44 Patients should be considered infectious until all scabs separate. The U.S. Centers for Disease Control and Prevention (CDC) maintain planning guidance for smallpox and other contagious infectious diseases on their bioterrorism website (http://emergency.cdc.gov/agent/smallpox/prep). Victims of an attack using weaponized smallpox, as well as contacts of known smallpox cases, should be immunized and monitored for at least 17 days following the last known exposure, regardless of their vaccination status. If fever manifests, they should be immediately isolated using contact and airborne precautions. Isolation should continue until smallpox is either ruled out or confirmed, and, if confirmed, until all scabs separate.
In 2007, the FDA licensed ACAM2000™ for smallpox vaccination, replacing the previously licensed vaccine (Dryvax®). In addition, the U.S. government purchased and stockpiled IMVAMUNE® smallpox vaccine for use in a public health emergency involving smallpox. ACAM2000, unlike previous smallpox vaccines, is grown in cell culture. It is administered via intradermal inoculation using a bifurcated needle – a process known as scarification. Primary vaccinees receiving ACAM2000 are given three punctures with the needle, while repeat vaccinees receive fifteen. The typical reaction to the vaccine includes appearance of a pruritic vesicle at the inoculation site 5–7 days following administration. Local erythema, pain, and induration as well as fatigue, axillary lymphadenopathy, and mild systemic symptoms to include fever, malaise, headache, and myalgias are common. Over the ensuing several days, the vesicle progresses to form a pustule, then a 3–10-mm scab which sloughs within 1–2 weeks, leaving a permanent scar. The lesion contains live vaccinia virus and spread of infection via contact is possible until the scab has separated.
Historically, with the previously employed Dryvax vaccine, serious adverse reactions occurred in approximately 1 per 1,000 patients immunized, with 1–5 of 10,000 immunizations leading to life-threatening complications, and 1 in a million leading to death. Serious reactions were approximately ten times more common in those being immunized for the first time than in those undergoing re-immunization. Adverse events have occurred with ACAM2000 vaccine, and are expected to occur at similar rates as Dryvax, since the same viral strain is used in both vaccines.45 Inadvertent autoinoculation of the virus to distant skin sites, as well as transfer of virus to contacts, has occurred historically in about 6 per 10,000 vaccines; ocular vaccinia is the most common form of inadvertent inoculation and can result in permanent corneal scarring. Generalized vaccinia results from systemic spread of the virus to produce lesions removed from the primary vaccination site; it occurs in 3 of 10,000 vaccinees. Post-vaccinial encephalitis is seen in approximately 1 per 100,000 primary vaccinees and has a 25% mortality rate, with another 25% developing permanent neurologic sequelae. Fetal vaccinia is a rare (<50 reported cases) but often fatal complication of maternal vaccination, most commonly reported in the third trimester of pregnancy. During a smallpox vaccination campaign in 2003, myopericarditis was reported in approximately 1 in 10,000 primary vaccinees in the United States, a rarely reported adverse event in previous programs.46–48 Eczema vaccinatum (generalized cutaneous spread of vaccinia in patients with eczema), a potentially lethal complication, can occur after vaccination in patients with a history of eczema. For this reason, CDC states that eczema is a contraindication to vaccination. Progressive vaccinia is the systemic spread of vaccinia virus in immunocompromised individuals, seen in 1 per million primary vaccinees and almost uniformly fatal.46–48
CDC’s Advisory Committee on Immunization Practices recommends that laboratory workers who directly handle live, unattenuated Orthopox virus cultures or infected animals, as well as select healthcare workers who are members of smallpox response teams, receive ACAM2000. Vaccination with a verified clinical “take” (vesicle with scar formation) within the past 3 years is considered to render a person immune to natural variola.
Preexposure vaccination is contraindicated in persons with the following conditions: immunosuppression (including those taking immunosuppressive drugs such as corticosteroids or alkylating agents), HIV infection, clinical evidence or history of eczema or other chronic exfoliative skin disorders, pregnancy or breastfeeding, and age less than 1 year. Additionally, the presence of household, sexual, or other close physical contacts with these conditions are contraindications to preexposure vaccination. There are no absolute contraindications to vaccination after bona fide exposure to variola. Vaccination after exposure to weaponized smallpox or to a person with smallpox may prevent or ameliorate disease if given promptly. Vaccination is likely to be most effective if given within 24 hours, but may still be somewhat effective from 4–7 days after exposure.49
A formulation of intravenous Vaccinia Immune Globulin (VIG) is licensed by FDA for treatment of certain complications of smallpox (vaccinia) vaccination, including generalized vaccinia, eczema vaccinatum, and progressive vaccinia. Public health professionals must have ready access to VIG when initiating vaccination programs. VIG is available as an IND through both DOD and CDC for intramuscular (IM) injection. An intravenous formulation of VIG (IV-VIG) is being produced to support the treatment of adverse events that may result from smallpox vaccination, and is also available under IND protocols from both CDC and DOD. The dose is 100 mg/kg for the intravenous formulation termed VIG-IV (first line, if available). If VIG-IV is unavailable, cidofovir can be used for treatment of vaccine adverse events (second line). The VIG-IM formulation is dosed at 0.6 ml/kg (third line), and due to its large volume (42 ml in a 70 kg person), should be given in multiple sites over 24–36 hours. Limited data suggest that VIG may also be of value in post-exposure prophylaxis against smallpox when given within the first week after exposure, and concurrently with vaccination. Concomitant administration of VIG may be particularly useful for pregnant and eczematous persons in such circumstances.50,51 Early vaccination alone is recommended for those without contraindications to the vaccine. If more than 1 week has elapsed after exposure, administration of both products (vaccine and VIG), if available, is a reasonable approach.52
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