REVIEW

Anthrax, , plague, or smallpox as agents of bioterrorism: recognition in the emergency room B. A. Cunha

Infectious Disease Division, Winthrop-University Hospital, Mineola and State University of New York School of Medicine, Stony Brook, New York, USA Bioterrorism has become a potential diagnostic consideration in infectious diseases. This article reviews the clinical presentation and differential diagnosis of potential bioterrorist agents when first presenting to the hospital in the emergency room setting. The characteristic clinical features of inhalation anthrax, tularemic , plague pneu- monia, including laboratory and radiographic finding, are discussed. Ebola vieus and smallpox are also discussed as potential bioterrorist-transmitted from the clinical and epidemiologic standpoint. In addition to the clinical features of the infectious diseases mentioned, the artical discusses the infectious disease control and epidemiologic implications of these agents when employed as bioterrorist agents. The review concludes with suggestions for postexposure prophylaxis and therapy. Keywords Anthrax, Bioterrorism, Plague, Ebola, Smallpox, Tularemia, Zoonoses, Zoonotic/Atypical Clin Microbiol Infect 2002; 8: 489–503

The emergency room is the most likely place tions early in an attack. The initial function of where victims of bioterrorism will first be encoun- physicians and consultants at the emergency room tered and evaluated. As we have learned from the level would be to identify sentinel cases involved anthrax experience in New York, mass casualties in the bioterrorism attack. It is critical to recognize are not necessarily to be expected. Even if large that a problem exists and will soon involve larger numbers of individuals are involved in a bioter- numbers of individuals. Aside from clinical recog- rorist attack, the initial cases will present as iso- nition of the of agents related lated incidents or irregularly in low numbers. to bioterrorism, the emergency room has an Once an outbreak is identified, then it is relatively important control role. Infectious disease easy to disseminate information on the nature of clinicians will be essential to assist their emer- the infectious disease agent, in terms of its recog- gency room colleagues, and infection control per- nition and control. Emergency room personnel, sonnel will be needed to limit the spread of with the assistance of infectious disease clinicians, biological agents within the emergency room set- are the sentinels at the gate. ting to other patients as well as medical personnel. Biological agents for potential use in bioterror- Containment measures will be particularly impor- ism are many. Some are more readily available and tant with biological agents that are transmitted via easier to employ than are others. The most likely the airborne route, or by person-to-person contact. agents to be involved in bioterrorism attacks Finally, general supportive measures and specific include Bacillus anthracis, pestis, Clostri- antimicrobial therapy, antitoxins or vaccines will dium botulinum, , and possibly be needed to treat the affected patients, and this the viral agents of African hemorrhagic . The treatment will begin in the emergency room. emergency room, as the initial point of contact for Emergency room personnel will need the early most bioterrorism victims, has three critical func- and substantial support of specialists related to the problems encountered with the various bioterror- Corresponding author and reprint requests: B. A. Cunha, ist agents. Infectious disease consultants will be Infectious Disease Division, Winthrop-University Hospital, Mineola, NY 11501, USA critical in the evaluation of all potential or real Tel: þ1 516 663 2505 bioterrorist cases. Infection control, as mentioned Fax: þ1 516 663 2753 previously, will be essential in containing the

ß 2002 Copyright by the European Society of Clinical Microbiology and Infectious Diseases 490 Clinical Microbiology and Infection, Volume 8 Number 8, 2002 infection where appropriate, to prevent loss by advised to rule out other neurologic conditions illness of critical medical personnel during an with similar features. Respiratory paralysis may outbreak. Physicians with experience in - occur in severe cases. Importantly, mental status is mediated diseases will also be needed if these unaffected by botulism; no signs of encephalitis or agents are employed in a bioterrorism attack. encephalopathy are present, and nuchal rigidity is On-going supportive care will be needed in the not present, i.e. there is no evidence of meningitis. management phase for those severely affected by The is 10–12 h, but this will not the attack. The emergency room also requires be helpful in the initial evaluation of the patient. intensive support from the microbiology labora- The incubation period is inversely proportional to tory, and must be in communication with autho- the quantity of toxin ingested. Some patients may rities to alert others of potential or actual threats have profuse vomiting without . Differ- from biological weapons [1–8]. ential diagnostic possibilities include bulbar palsy, Guillain–Barre syndrome, or polio, but these con- BIOLOGICAL WEAPONS ditions do not closely resemble botulism. Guillain– TRANSMITTED BY FOOD OR WATER Barre syndrome is usually accompanied by some degree of , has a sensory component, and botulinum characteristically begins as ascending rather than C. botulinum is a spore-forming organism that descending paralysis. Diagnosis of botulism is produces a potent exotoxin. The exotoxin is ther- confirmed by detecting botulism toxin in the stool molabile, but is extremely potent. Minute or serum [9–13]. amounts, if properly dispersed and disseminated, would be sufficient to eliminate the entire human population. Highly purified botulism toxin is Enteropathogens stable, easily transportable, and readily dispersed. Toxigenic or enteropathogenic , Sal- Ideal vehicles for the transmission of the toxin monella or are potential biological would be water supplies and selected food items, weapons. Such agents would have to be intro- but fortunately, such transmission is difficult to duced into water supplies in large numbers to achieve. Food-borne botulism requires the intro- be recognized as biological weapons. At any given duction of the toxin into foods at the level of the time, there are sufficient sporadic cases of poorly packing plant. This would require terrorists using characterized febrile diarrheal illnesses in the this to have access to such a population to make the detection of these agents facility. In contrast, water-borne botulism toxin difficult. Only if they occurred in large num- would be much easier to use, but because of bers, suggesting an outbreak, could the possibility difficulties with dispersal of the toxin in large of bioterrorist be entertained. Clinicians are famil- volumes of water, it would be difficult to utilize. iar with the clinical presentation of these infecti- Botulism toxin could be easily placed in reservoirs ous diseases and they are rarely fatal. The use or water tanks, but would not mix completely or of enteropathogens as biological weapons would evenly in the target volume of water. Therefore, create anxiety and cause some illness, but water-borne botulism is likely to occur as sporadic would be minimally disruptive to society. When attacks, since it is unlikely that large numbers of these infectious diseases are not self-limited, people would be affected simultaneously, due to they are readily treatable with antimicrobial the difficulties in dispersing the toxin in large agents [4–6]. volumes of water. In the emergency room, botu- lism will present as descending symmetric paraly- BIOLOGICAL WEAPONS sis, starting with cranial nerve involvement. Onset TRANSMITTED BY CONTACT would be heralded by the presence of blurry vision, which is rapidly followed by ocular muscle Ebola/viral hemorrhagic fevers paralysis, difficulty in speaking, and/or the inabil- Person-to-person transmission is a potential way ity to swallow. Fever is not a feature of botulism, to spread some bioterrorist agents, particularly since it is a toxin-mediated disorder. There are few and agents of African hemor- other conditions that could be confused with botu- rhagic fevers. These agents are highly contagious lism clinically, but neurologic consultation is and difficult to handle, and because of this are not

ß 2002 Copyright by the European Society of Clinical Microbiology and Infectious Diseases, CMI, 8, 489–503 Cunha Bioterrorism in the emergency room 491 likely to be utilized as biological weapons. Ebola develop a camelback fever curve, and a pulse fever, Rift Valley fever, etc. could be transmitted temperature deficit (relative bradycardia). Ebola by a terrorist willing to be infected by these agents. and related hemorrhagic fevers are often accom- The terrorist would have to travel to the intended panied by leukopenia, lymphopenia, and throm- area during the incubation period of the infection bocytopenia; these are important laboratory clues in order to initiate person-to-person transmission, to help the clinician differentiate these illnesses by secretion contact and/or, to a lesser extent, by from sporadic cases of gastroenteritis in the com- airborne dissemination. Ebola fever begins with munity. By the time that petechiae/ecchymoses or severe and fever, followed quickly by diatheses appear, the diagnosis should be gastrointestinal symptoms, usually accompanied obvious. Clinical diagnosis is confirmed by sero- by nausea and vomiting. As Ebola fever pro- logic testing. With suspected African hemorrhagic gresses, fever and severe myalgias remit for a fevers, patients should be subjected to strict few days, and then the patient worsens. Liver airborne isolation and contact precautions until involvement and bleeding problems characterize the diagnosis is ruled out. Specimens sent to the late stages of advanced Ebola fever. Physicians the laboratory should be considered as extremely in the emergency room should be suspicious of biohazardous and handled accordingly. There is patients with the abrupt onset of a severe illness no specific treatment for any of the viral hemor- characterized by headache, myalgias, and nausea rhagic fevers, and therapy is supportive [14–20] and vomiting. Over several days, patients may (Table 1).

Table 1 Differential diagnosis of African hemorrhagic fever

Yellow fever Lassa fever Ebola virus

Location Central Africa West Africa East Africa East Africa Onset Sudden Gradual Sudden Sudden Symptoms Severe headache/ þþþ þ myalgias/lumbar backache Tinnitus ÀþÀ À Sore throat Àþþ þ Dry cough/chest pain Àþþ þ Nausea/vomiting/ þÀþ þ abdominal pain Diarrhea ÀÆþ þ Renal failure ÀÀþ þ Signs Relative bradycardia þþþ þ Biphasic fever pattern þþþ þ Conjunctivitis Àþþ þ Conjunctival suffusion þþþ þ Rash ÀÀScarlatiniform Maculopapular Adenopathy À Cervical Generalized À Facial/neck edema ÀþÀ À Laboratory abnormalities Leukopenia ! leukocytosis þþþ þ Atypical lymphocytosis þþþ þ Thrombocytopenia þþþ þ "SGOT þþþ þ Late complications If not death Iritis, Myocarditis, Extreme from acute deafness, orchitis malaise, hepatic ARDS, desquamation, profound , seizures, scrotal/labial loss of none oculogyric dermatitis, appetite crises ARDS

Reproduced with permission from: Gill MV, Cunha BA. Ebola hemorrhagic fever. Infect Dis Practice 1995; 19: 37–41.

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BIOLOGICAL WEAPONS lesions crust. The treatment of smallpox is cur- TRANSFERRED BY THE rently symptomatic. Although cidofovir has in AIRBORNE ROUTE vitro activity against the smallpox virus, it is fairly toxic and can only be administered intravenously. Smallpox Children and young adults have not been vacci- Like most infectious diseases, smallpox is most nated against smallpox. The immunity of older contagious during the incubation period before the adults previously immunized against smallpox is onset of the rash. The initial patients in a biological not known at the present time. If smallpox is attack using smallpox will present before the rash identified in a patient, it must be assumed to appears. The rash in smallpox does not appear for represent a bioterrorism attack, since natural cases at least 3 days after the on-set of symptoms. no longer exist. Accordingly, officials must be Patients initially complain of headache and myal- contacted for immediate distribution of the small- gias, and may have a diffuse maculopapular rash pox vaccine. Some older individuals may develop prior to their subsequent vesicular eruption. immunity more rapidly than their younger coun- Fevers are high and have a characteristic pattern. terparts, due to the anamnestic response to The fever initially decreases without treatment on the previous smallpox vaccine [21–26] (Table 2, day two, before increasing again prior to the vesi- Figure 1). cular eruption on or after day three. Patients may complain of gastrointestinal symptoms at the out- set of the illness. Patients also appear irritable and Tularemia uncomfortable before the rash appears. The F. tularensis is a highly virulent organism with appearance of the rash is heralded by a decrease different manifestations depending upon inocu- in temperature and the appearance of vesicles lum/site of infection. It is unlikely that F. tularensis beginning on the head and face. Vesicles increase would be used as a weapon of bioterrorism, since it and become prominent on the chest, have a cen- has no stable spore phase, and is highly virulent trifugal distribution on the extremities, and and difficult to handle. It would be difficult to involve the palms and the soles. In the early aerosolize this organism without infecting those vesicular stage, smallpox is most likely to be con- processing and handling the organism for use in fused with chicken pox. The constitutional symp- . Should tularemia be used, toms, as well as the distribution of the rash, readily aerosol spread would be the most likely mode differentiate it from other vesicular rashes, e.g. orf, of deployment. In the emergency room, patients dermatitis, or herpetiformis, and atypical . would present with an atypical pneumonia. Most In chicken pox, the rash progresses in successions clinicians are now familiar with the fact that aty- of crops of new vesicles every few hours, and pical pathogens are characterized by extrapulmon- abruptly stops after 3 days. The vesicles are not ary manifestations. The most common atypical as large or umbilicated as in smallpox. Patients are pneumonias encountered in the emergency room not as toxemic in appearance as with smallpox. setting are pneumoniae pneumonia and The vesicles of chicken pox resemble a dewdrop legionnaires’ disease. Legionnaires’ disease is on a rose petal, and lesions in chicken pox all most likely to be confused with tularemic pneu- present at different stages of eruption. In smallpox, monia, but these two may be differentiated fairly characteristically, the lesions, are all in the same well by clinical signs and symptoms. Patients with stage of development when they appear. Hemor- tularemia, in contrast to those with legionnaires’ rhagic smallpox may present with diffuse bleeding disease, have a clear sensorium, but both may into the skin. Smallpox and chicken pox are clinical present with a headache. The headache of tular- diagnoses. If there is any confusion in differentiat- emia, however, is severe and usually associated ing the two, a Tzanck test should be performed. with prominent myalgias. The chest X-ray pattern Cytoplasmic inclusion bodies seen in stained of tularemic pneumonia is nondescript, as is that of scrapings from the vesicle base are present in legionnaires’ disease. Infiltrates in tularemic pneu- chicken pox but not in smallpox. Both chicken monia may be unilateral or bilateral, but they are pox and smallpox are highly contagious via the usually accompanied by pleural effusion and/or airborne route, and require strict airborne isola- hilar adenopathy. Tularemic pneumonia is more tion. Patients are no longer contagious after the likely to be confused with inhalation anthrax than

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with legionnaires’ disease. Both inhalation anthrax and tularemic pneumonia have mediastinal widening and pleural effusions as common fea- tures. In legionnaires’ disease, serum transami- nases are frequently mildly and transiently elevated, in contrast to tularemic pneumonia, in which the serum transaminases remain normal. Relative bradycardia is a cardinal feature of legion- naires’ disease but is not characteristic of tulare- mia. Increases in CPK, erythrocyte sedimentation rate, and CRP, and a decreased serum phosphorus, strongly favor the diagnosis of legionnaires’ dis- ease versus tularemia, anthrax, or typical bacterial Postexposure prophylaxis of medical contacts Smallpox vaccination recommended, if unable to takevaccine (compromised hosts) administer vaccinia immune globulin (VIG) 0.6 mL/kg (IM) inover 2 24 h divided doses pneumonias. If the pleural effusions are tapped, the pleural effusions of tularemia are sero-sangui- nous or frankly hemorrhagic, which is uncommon with other pulmonary infections, except for inha- lation anthrax. F. tularensis is readily treatable, if recognized early, with . Quinolones probably represent an acceptable alternative in doxycycline-intolerant patients. From the infection control standpoint, the main biohazard presented by tularemia is in the handling of specimens by personnel in the emergency room and microbiol- ogy laboratory [27–35] (Tables 3–5). Sodium hypochlorite or quaternary ammonia compounds Clothing/ bedding should be washedhot in water with bleach/autoclaved Use biohazard bags for all else Recommended disinfection procedures

Plague pneumonia Pneumonic plague would be a devastating agent to use in biological warfare. Unlike bubonic pla- gue, pneumonic plague has the potential for per- Standard universal precautions Airborne Isolation Infection control precautions son-to-person airborne spread. If plague is transmitted in this fashion, it has great potential for spreading. However, Y. pestis has no spore stage, and is difficult to process, handle and dis- perse if used in aerosol form. Should anyone in a non-endemic area develop pneumonic plague that is not a complication of an ongoing High Potential for patient-to-medical personnel spread , then the plague may be considered to be the result of the bioterrorism. Plague pneumonia is nondescript in terms of chest X-ray appearance. Patients are critically ill. The is pink and frothy and contains abundant bipolar-staining Gram-negative bacilli. Hilar adenopathy and pleural effusions are not features of pneumonic High Potential for patient-to-patient spread plague. Circulatory collapse is common as the infection progresses, as is the case with inhalation anthrax. Diagnosis is established by demonstrat- ing the organism in sputum or blood samples. Smallpox: infection control considerations Plague may be treated with or dox- ycycline. From an infection control standpoint, Emergency room/ hospital Table 2 person-to-person spread of plague from patients

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Figure 1 Smallpox: relationship of fever to signs and symptoms. Reproduced with permission from: Cunha BA. Smallpox: an osterian primer. Infect Dis Practice 2002; 26. with pneumonic plague may be contained by incident occurring in Sverdlosk in the Soviet using appropriate airborne precaution procedures Union due to an accident at a biological weapons [36–44] (Tables 6–8). facility, the New York experience is the only care- fully studied and reported experience with inhala- tion anthrax from the inhalation of weapons-grade Anthrax spores. Patients presenting with inhalation an- Because anthrax is a naturally occurring infectious thrax do not feel well for several days during disease, there is much experience with recognizing the prodromal period, and frequently complain and treating naturally acquired inhalational and of substernal discomfort and fever; sometimes, cutaneous anthrax. However, in the 2001–2002 US gastrointestinal symptoms are present at this experience, weapons-grade anthrax was used as a stage. Patients still do not feel well, but subse- weapon of bioterrorism for the first time. Cuta- quently improve over the next day or two, and neous anthrax derived from weapons-grade then in most cases the infection progresses. anthrax is clinically the same as naturally acquired The second phase of anthrax is characterized by cutaneous anthrax. However, the clinical presen- high fever, oppressive sternal chest pain mimick- tation of inhalational anthrax due to weapons- ing an acute myocardial infarction, and shortness grade B. anthracis spores is different from that of of breath. Chest X-ray may reveal small bilateral cases previously occurring with naturally ac- pleural effusions, with or without a widened med- quired inhalation anthrax. Except for the previous iastinum. Since inhalation anthrax results in a

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Table 3 Tularemia: empirical therapy for presumed tularemic pneumonia

Total duration of Exposed hosts Preferred initial therapy IV ! PO switch therapy (IV/PO)

Adults Streptomycin 1 g (IM) NA 10 days every 12 h or 5 mg/kg (IM/IV) NA 10 days every 24 h or Doxycycline 200 mg (IV) Doxycycline 100 mg (PO) 14 days every 12 h every 12 h or or 500 mg (IV) Chloramphenicol 250 mg (PO) 14 days every 6 h every 6 h or or Ciprofloxacin 400 mg (IV) Ciprofloxacin 500 mg (PO) 10 days every 12 h every 12 h or or 500 mg (IV) Levofloxacin 500 mg (PO) 10 days every 24 h every 24 h or or Gatifloxacin 400 mg (IV) Gatifloxacin 400 mg (PO) 10 days every 24 h every 24 h Children >12 years Same as adults <12 years Streptomycin 15 mg/kg (IM) NA 10 days every 12 h or Gentamicin 5 mg/kg (IM/IV) NA 10 days every 24 h or Doxycycline 2.2 mg/kg (IV) Doxycycline 2.2 mg/kg (PO) 14 days every 12 h every 12 h or Ciprofloxacin 30 mg/kg (IV) Ciprofloxacin 30 mg/kg (PO) 10 days every 12 h every 12 h or Levofloxacin 250 mg (IV) Levofloxacin 250 mg (PO) 10 days every 24 h every 24 h or Gatifloxacin 200 mg (IV) Gatifloxacin 200 mg (PO) 10 days every 24 h every 24 h

Table 4 Tularemia: infection control considerations

Potential for Potential for Infection Recommended Post-exposure patient-to-patient patient-to-medical control disinfection prophylaxis of spread personnel spread precautions procedures medical contacts

Emergency room/ None None Standard Sodium hypochlorite þ hospital universal or precautions quaternary ammonia compounds (avoid aerosolization of infectious materials)

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Table 5 Tularemia: postexposure Preferred Duration of prophylaxis Post-exposure host prophylaxis

Adults (normal/compromised Doxycycline 100 mg (PO) 14 days hosts) every 12 h or 14 days Ciprofloxacin 400 mg (PO) every 12 h or Levofloxacin 500 mg (PO) 14 days every 24 h or Gatifloxacin 400 mg (PO) 14 days every 24 h Children (normal/compromised hosts) >12 years Same as adult <12 years Amoxicillin 40 mg/kg (PO) 14 days every 8 h or Ciprofloxacin 30 mg/kg (PO) 14 days every 12 h or Levofloxacin 250 mg (PO) 14 days every 24 h or Gatifloxacin 200 mg (PO) 14 days every 24 h

hemorrhagic mediastinitis and not pneumonia, inhaled weapons-grade spores is sufficiently high, demonstration of a widening mediastinum should a localized pneumonitis in the segment of the suggest the diagnosis of inhalation anthrax in receivingthehighsporeconcentrationcanresultina acutely ill febrile patients. The mediastinal widen- pulmonary infiltrate in addition to the findings of ing due to hemorrhagic mediastinitis is detected hemorrhagic mediastinitis described. earliest and best by chest CT/MRI. As mention- Anthrax meningitis frequently accompanies ed previously, the hemorrhagic mediastinitis cases of inhalation anthrax, so emergency room may be inapparent or minimally apparent on physicians must be alert to patients presenting the conventional chest X-ray, and if there is any with central nervous system findings in addition question about the possibility of anthrax or inter- to their pulmonary symptoms. In some cases, pretation of the plain film, then a chest CT/MRI anthrax hemorrhagic leptomeningitis occurs alone should be obtained immediately. Liver function and/or overshadows the pulmonary component tests have been reported as being abnormal in of the infection. Lumbar puncture performed in inhalation anthrax cases; otherwise, routine patients with anthrax meningitis reveals a PMN laboratory tests are unhelpful, except for throm- predominance and abundant red blood cells. The bocytopenia, which is a variable finding. In hemor- cerebrospinal fluid (CSF) glucose is depressed, rhagic mediastinitis, the fact that the inhaled and the CSF protein is variably elevated. A Gram spores have been milled to a very small diameter stain of the CSF shows Gram-positive bacilli. In the and processed with a surface tension-reducing Sverdlosk experience, anthrax meningitis was agent allows individual spores to reach the alveoli. readily diagnosed at autopsy in patients who died The spores are ingested by the alveolar macro- of anthrax meningitis. The characteristic appear- phages and transported via the lymphatics to the ance has been termed ‘the cardinal’s cap’, in which lymph nodes of the mediastinum. There they there is hemorrhage diffusely over the brain, invol- interfere with hemostasis locally, resulting in hemo- ving the leptomeninges. This finding may be use- rrhage at the mediastinum. If the inoculum of ful in terms of retrospective diagnosis, but is

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Table 6 Empirical therapy for presumed plague

Total duration of Exposed hosts Preferred initial therapy IV ! PO switch therapy (IV/PO)

Adults Streptomycin 1 g (IM) NA 10 days every 12 h or Gentamicin 5 mg/kg (IM/IV) NA 10 days every 24 h or Doxycycline 200 mg (IV) Doxycycline 100 mg (PO) 14 days every 12 h every 12 h or or Chlorophenicol 500 mg (IV) Chloramphenicol 250 mg (PO) 14 days every 6 h every 6 h or or Ciprofloxacin 400 mg (IV) Ciprofloxacin 500 mg (PO) 10 days every 12 h every 12 h or or Levofloxacin 500 mg (IV) Levofloxacin 500 mg (PO) 10 days every 24 h every 24 h or or Gatifloxacin 400 mg (IV) Gatifloxacin 400 mg (PO) 10 days every 24 h every 24 h Children >12 years Same as adult <12 years Streptomycin 15 mg/kg (IM) NA 10 days every 12 h or Gentamicin 5 mg/kg (IM/IV) NA 10 days every 24 h or Doxycycline 2.2 mg/kg (IV) Doxycycline 2.2 mg/kg (PO) 14 days every 12 h every 12 h or or Ciprofloxacin 30 mg/kg (IV) Ciprofloxacin 30 mg/kg (PO) 10 days every 12 h every 12 h or or Levofloxacin 250 mg (IV) Levofloxacin 250 mg (PO) 10 days every 12 h every 24 h or or Gatifloxacin 200 mg (IV) Gatifloxacin 200 mg (PO) 10 days every 24 h every 24 h or or Chloramphenicol 25 mg/kg (IV) Chloramphenicol 25 mg/kg (PO) 14 days every 6 h every 6 h

Table 7 Plague: infection control considerations

Potential for Potential for Infection Recommended Post-exposure patient-to- patient-to-medical control disinfection prophylaxis of patient spread oersonnel spread precautions procedures medical contacts

Emergency room/ Low Low Standard Sodium hypochlorite þ hospital universal or (during first 48 h precautions quaternary ammonia of antibiotic plus surgical compounds therapy) masks

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Table 8 Plague: post-exposure pro- Duration of phylaxis Post-exposure host Preferred antibiotic prophylaxis

Adults (normal/compromised Doxycycline 100 mg (PO) 7 days hosts) every 12 h or Ciprofloxacin 400 mg (PO) 7 days every 12 h or Levofloxacin 500 mg (PO) 7 days every 24 h or Gatifloxacin 400 mg (PO) 7 days every 24 h or Chloramphenicol 500 mg 7 days (PO) every 6 h Children (normal/compromised hosts) >12 years Same as adult <12 years Doxycycline 2.2 mg/kg (PO) 7 days every 12 h or Ciprofloxacin 30 mg/kg (PO) 7 days every 12 h or Levofloxacin 250 mg (PO) 7 days every 24 h or Gatifloxacin 200 mg (PO) 7 days every 24 h or Chloramphenicol 25 mg/kg 7 days (PO) every 6 h

unhelpful in the initial management in the emer- The presumptive diagnosis of anthrax depends gency room setting (Table 9). on demonstrating Gram-positive bacilli under If anthrax spores are ingested, gastrointestinal the eschar in cutaneous anthrax, or in the CSF in anthrax may result, but this would be exceedingly anthrax meningitis, or in the blood in bacteremic uncommon. Gastrointestinal anthrax is character- or septicemic anthrax. The sputum does not ized by a single large lesion, not unlike the cuta- usually contain B. anthracis in inhalation anthrax. neous lesion of anthrax, but which is present in the Samples of body fluids should be considered to gastrointestinal tract. There is usually a single, be extremely biohazardous, and the microbio- large present, which may hemorrhage. Bac- logy laboratory should be warned prior to speci- teremia may complicate any clinical type of mens are being sent to them from the emergency anthrax, and is overwhelming in septicemic room. The presumptive diagnosis of anthrax anthrax. When there is hematogenous dissemina- depends on demonstrating hemolysis on blood tion from the skin or the , some of the organ- agar. Other tests suggested for anthrax in Gram- isms localize to the gastrointestinal tract. For this positive bacilli are the demonstration of a cap- reason, in cases of anthrax it is not uncommon to sule using a negative stain, e.g. Congo red or find multiple small hemorrhagic ulcers through- India ink, or the demonstration of the character- out the gastrointestinal tract. This is in contrast to istic fir tree appearance of gelatin liquefaction the single predominant lesion found when the in a stat gelatin culture tube. Serologic tests organisms are ingested and do not reach the intes- for anthrax usually take some time and are tine via the bloodstream. unhelpful in the initial management of patients.

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Table 9 Diagnostic approach to biological agents transmitted by inhalation

Plague Tularemia Legionella Anthrax

Symptoms Sore throat ÀÆ ÀÆ Shortness of breath þÆ Àþ Hemoptysis þþ Àþ Chest pain þþ Æ Æ þþþ Abdominal pain þÀ ÆÆ Nausea/vomiting þÀ ÆÆ Diarrhea þÀ þÆ Signs Relative bradycardia ÀÀ þÀ Shock þÆ Àþ Laboratory features Sputum Hemorrhagic Hemorrhagic Mucoid/purulent Hemorrhagic (raspberry syrup sputum) Gram stain sputum Gram-negative Gram-negataive Negative/normal Gram-positive coccobacilli coccobacilli flora bacilli (bipolar staining) (non-bipolar staining) Blood cultures þÀ Àþ Chest X-ray: Infiltrates Bilateral segmented/ Bilateral/segmented/ Multilobar Usually none lobar lobar (À consolidation) infiltrates (if present, focal (Æ consolidation infiltrates) infiltrates) Mediastinal widening Pleural effusion Àþ(Bilateral bloody) Æ (Non-bloody) þ (Bilateral bloody) BHA Àþ ÀÀ WBCs " LFTs ÀÀ þþ " CPK ÀÀ þÀ # PO4 ÀÀ þÀ

BHA, bilateral hilar adenopathy. Reproduced with permission from: Cunha BA. Bioterrorist anthrax: a clinical prespective (Part II). Infect Dis Practice 2002; 26: 81–85.

Specimens that are presumptively identified as Table 10 Microbiological differences between B. anthracis being positive for anthrax should be forwarded and non-B. anthracis bacilli to central laboratories for definitive identification B. anthracis (Table 10). Non-motile/encapsulated/long chains Fortunately, B. anthracis is susceptible to the No growth on penicillin agar (10 mg/mL) majority of . The organism is exquisitely ‘Inverted fir-tree’ growth in gelatin Gelatin liquefaction slow sensitive to penicillin and most b-lactams. The No hemolysis of sheep red blood cells most extensive experience in treating anthrax Ferments salicin slowly or not at all has been with penicillin and with doxycycline. Pathogenic to laboratory animals In the recent New York experience, quinolones Non-B. anthracis (pseudo-anthrax bacilli) were used. Some patients were treated with dou- Generally motile/non-encapsulated/short chains ble-drug therapy, but there is little evidence to Usually good growth on penicillin agar support this approach. B. anthracis is so exquisitely Growth absent or atypical fir tree in gelatin Gelatin liquefaction usually rapid sensitive that consideration of synergy is irrele- Hemolysis of sheep red blood cells vant. In some patients, clindamycin was added to Usually ferment salicin rapidly the regimen for its purported anti-endotoxin activ- Non-pathogenic to laboratory animals ity rather than its antibacterial effects. Reproduced with permission from: Cunha CB. Anthrax: Because of earlier treatment and recognition, ancient plague, persistent problem. Infect Dis Practice 1999; rather than because of more efficacious antibacter- 23: 35–9.

ß 2002 Copyright by the European Society of Clinical Microbiology and Infectious Diseases, CMI, 8, 489–503 500 Clinical Microbiology and Infection, Volume 8 Number 8, 2002 ial therapy, the fatality rate with inhalation SYNDROMIC CLINICAL anthrax in the New York experience was better DIAGNOSTIC AND THERAPEUTIC than had been previously reported. APPROACH From an infection control standpoint, inhala- tion anthrax and cutaneous anthrax are not Bioterrorism in the emergency room presents spe- very contagious, but the potential for contag- cial challenges. The main focus of emergency room iousness exists via organism- or spore-contami- personnel in a possible bioterrorism attack is to nated/infected body fluids [45–53] (Tables 11– quickly and rapidly arrive at a presumptive diag- 13). nosis of the agents involved. Early recognition

Table 11 Anthrax: empirical therapy for presumed anthrax pneumonia

Total duration of Exposed hosts Preferred initial therapy IV ! PO switch therapy (IV/PO)

Adults Doxycycline 200 mg (IV) Doxycycline 100 mg (PO) 14 days every 12 h every 12 h or or Penicillin G 4 MU (IV) Amoxicillin 1 g (PO) 14 days every 4 h every 8 h or or Ciprofloxacin 400 mg (IV) Ciprofloxacin 500 mg (PO) 14 days every 12 h every 12 h or or Levofloxacin 500 mg (IV) Levofloxacin 500 mg (PO) 14 days every 24 h every 24 h or or Gatifloxacin 400 mg (IV) Gatifloxacin 400 mg (PO) 14 days every 24 h every 24 h Children >12 years Same as adult <12 years Doxycycline 2.2 mg/kg (IV) Doxycycline 2.2 mg/kg (PO) 14 days every 12 h every 12 h or or Penicillin 50 000 U/kg (IV) Amoxillin 40 mg/kg (PO) 14 days every 6 h every 8 h or or Ciprofloxacin 30 mg/kg (IV) Ciprofloxacin 30 mg/kg (PO) 14 days every 12 h every 12 h or or Levofloxacin 250 mg (IV) Levofloxacin 250 mg (PO) 14 days every 24 h every 24 h or or Gatifloxacin 200 mg (IV) Gatifloxacin 200 mg (PO) 14 days every 24 h every 24 h

Adapted with permission from: Cunha BA. Anthrax. Antibiotic essentials. Birmingham MI, Physicians Press, 2002.

Table 12 Anthrax: infection control considerations

Potential for Potential for Infection Recommended Post-exposure patient-to-patient patient-to-medical control disinfection prophylaxis of spread personnel spread precautions procedures medical contacts

Emergency room/ Low Low Standard Sodium hypochlorite Unnecessary hospital universal or precautions quaternary ammonia compounds

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Table 13 Anthrax: post-exposure prophylaxis Duration of Post-exposure host Preferred antibiotic prophylaxis

Adults (normal/compromised Doxycycline 100 mg (PO) 60 days hosts) every 12 h or Amoxicillin 1 g (PO) 60 days every 8 h or Ciprofloxacin 400 mg (PO) 60 days every 12 h or Levofloxacin 500 mg (PO) 60 days every 24 h or Gatifloxacin 400 mg (PO) 60 days every 24 h Children (normal/compromised hosts) >12 years Same as adult <12 years Amoxicillin 40 mg/kg (PO) 60 days every 8 h or Ciprofloxacin 30 mg/kg (PO) 60 days every 12 h or Levofloxacin 250 mg (PO) 60 days every 24 h or Gatifloxacin 200 mg (PO) 60 days every 24 h

Reproduced with permission from: Cunha BA. Antibiotic essentials. Birming- ham, MI: Physicians Press, 2002. provides the ability to warn other centers to be pneumonia versus inhalation anthrax, or to sepa- watchful for patients with similar syndrome com- rate these entities from other conditions in the plexes. It also alerts hospital personnel to the community that may cause confusion in the emer- danger of infected patients, and alerts laboratory gency room setting, e.g. legionnaires’ disease ver- personnel to the danger of handling biohazardous sus tularemia. Except for botulism and the African materials. As is the case with other infectious hemorrhagic fevers, and smallpox, all of the diseases, differential diagnosis is the key function remaining agents likely to be used in bioterrorism of physicians and consultants. When an outbreak are , and are susceptible to antibiotics due to bioterrorism agent is well underway and (Table 14). understood, awareness is heightened and the like- While quinolones are preferable for enteral lihood of misdiagnoses decreases greatly. How- pathogens, and streptomycin is preferred for pla- ever, the real challenge comes in diagnosing the gue, doxycycline is the antibiotic most likely to be index cases correctly. Patients subjected to bioter- efficacious when a precise etiologic agent has not rorist agents are likely to present with either neu- yet been identified. Doxycycline, when used for rologic symptoms, e.g. botulism, or respiratory serious infections, is optimally given at a dose of symptoms, e.g. plague pneumonia, inhalation 200 mg intravenously every 12 h for 72 h. anthrax, tularemic pneumonia, gastrointestinal ill- Because the drug has a long half-life and is highly nesses, enteric pathogens, bleeding diatheses, such lipid soluble, this loading regimen needs to be as the African hemorrhagic fevers, or pneumonias, used in order to achieve a rapid therapeutic effect. such as tularemic pneumonia, inhalation anthrax, If a patient is given doxycycline, 100 mg intrave- or plague pneumonia. The most difficult diagnos- nously or orally every 12 h, as is usually recom- tic challenge would be to differentiate between mended, it will take 4–5 days before the maximum diseases that have similar features, e.g. tularemic therapeutic effect is achieved. This is far too long,

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Table 14 Differential diagnosis of Clinical syndrome Bioterrorist agents Non-bioterrorist mimic bioterrorist agents by clinical syn- drome on presentation to the emer- Severe headache/myalgias, Ebola Meningococcal gency room nausea, vomiting, Hemorrhagic smallpox meningitis/ generalized bleeding (pre-eruptive) meningococcemia Hemorrhagic measles Severe headache, myalgias, Smallpox Rocky Mountain and vomiting (pre-eruptive) (RMSF) Viral influenza Tick-borne arborviruses Weakness, blurry vision, Botulism Bulbar palsies dysphagia (massive CVA, ALS) Pseudobulbar palsies Community-acquired Plague pneumonia Pulmonary emboli/ pneumonia with Tularemia pneumonia infarction hemoptysis Community-acquired Plague pneumonia Legionella pneumonia with nausea, vomiting, diarrhea, abdominal pain Community-acquired Anthrax Acute MI pneumonia with chest pain/shock

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