Walter Pasini
This is the first time in history that the world is faced with bioterrorism and is concerned about the use of chemical and bacteriological weapons meant for mass destruction. Not only the armed forces are exposed, as it happened in the past on the occasion of the First World War and of certain local wars, but the entire civilian population is.
The threat for the civilian population had existed for some time, but it had never materialised. At the times of the cold war, United States and Soviet Union had launched a regular arm race for chemical and bacteriological weapons. To name but one example, at the same time in which the World Health Organisation announced in 1980 that smallpox had been eradicated and that vaccination was therefore no longer necessary, USSR was busy establishing other laboratories (besides the official one in Koltsovo which, together with the Atlanta one, was authorised to store Smallpox strains) for the production of tons of smallpox virus as a biological weapon. It was Nixon who, in 1969, asked for a suspension of this biological arm race, but this certainly did not stop in many other countries.
During the Gulf War, the Iraq government had admitted it possessed great quantities of anthrax and of botulin toxin, which they could spread by means long-range missiles.
Since then, American healthcare, and the Atlanta CDC in particular, have conducted in-depth studies on all aspects relating to the preparation for and reaction to bioterrorism. Since 1992, a great number of complex epidemics have occurred in the States. The list includes the epidemic involving over 400,000 cases of criptosporidiosis in Milwaukee, an epidemic relating to an unexplainable pulmonary affection that is now known as the hantavirus pulmonary syndrome in spring 1993, an epidemic spreading to the entire national territory of salmonellosis provoked by contaminated ice-cream, which caused in 1994 over 250,000 cases, the growing number of antibiotic-resistant microorganisms in hospitals and in the entire community. The plague epidemic in India, the Ebola haemorrhagic fever in Zaire, the H5N1 flue in Hong Kong, the Hendra virus infection in Australia and the Nipah infection in Malaysia and Singapore requested an immediate and complex response. The possibility of bioterrorism was taken into account in the study of these diseases, but no evidence emerged, and the possibility of bioterrorism was also investigated as the cause of the Western Nile fever which has already produced several victims in New York.
The CDC divides the biological agents that could be employed for bioterrorist purposes into different categories.
Category A includes organisms that:
- endanger national safety; person-to-person dissemination and transmission can easily take place;
- cause a high mortality rate;
- may generate public panic and social upheaval;
- require special action to implement an adequate public healthcare response.
The agents included in this category are:
- variola major (smallpox)
- bacillus anthracis (anthrax)
- versinia pestis (plague)
- clostridium botulinum (botulism)
- francisella tularensis (tularaemia)
- filovirus (haemorrhagic fever, Ebola and Marburg)
- arenavirus (Lassa fever, Argentinian haemorrhagic fever)
Category B includes second priority agents, which are moderately easy to disseminate, which cause moderate morbility and low mortality, and which require specific abilities in the field of laboratory diagnosis and of epidemiological control.
The following agents are included in group B:
- coxiella burnetti (Q fever)
- brucella (brucellosis)
-alfavirus (Venezuelan encephalomyelitis, equine encephalomyelitis)
- toxin from Ricinus communis (castor beans)
- epsilon toxin from clostridium perfrigens
- staphylococcus enterotoxin B
List B also includes pathogenic agents that may be transmitted through food and nourishment:
- salmonella
- shigella
- escherichia coli O157:H7
- vibrio cholerae
- cryptosporidium parvum
Category C includes emerging pathogenic agents that may be transformed through bioengineering for dissemination purposes, thanks to their availability, to the easiness with which they are produced and disseminated, to their high mortality and morbility potential and to their impact on public health.
Category C includes:
- the Nipah virus
- the hantaviruses
- hemorrhagic fever viruses transmitted by ticks
- the yellow fever virus
- multiresistent tuberculosis
The preparation for and ability to deal with bioterrorism provides for the need to be able to identify, diagnose and treat these pathologies. Of course, it is not always possible to know in advance which biological agents terrorists intend to use. It is however necessary to improve epidemiological surveillance of infectious diseases worldwide, especially as regards emerging and old diseases, the so-called re-emerging ones (anthrax, plague, smallpox, cholera, tuberculosis, etc.).
The preparation for chemical and bacteriological attacks is accomplished through the following plan of action:
- improve the epidemiological ability to identify and respond to biological attacks.
- supply diagnostical reagents to various category laboratories.
- draw up communication programmes at a national and international level.
- implement training programmes for health-care staff.
- obtain adequate supplies of antibiotics and vaccines.
- prepare educational material to inform and reassure the public during and after the biological attack.
- improve molecular surveillance over new bacterial strains, including unusual and multiresistent strains.
- support the research for new diagnostic tests.
- encourage the research on antiviral drugs and new vaccines.
A factor that appears to have great importance is that all medical practitioners possess a cultural background enabling them to promptly recognise and notify diseases that are rare or little known, which could however be deliberately provoked through terrorist attacks.
Table. 1 displays a list of biological agents which may potentially be employed for terrorist attacks. Table 2 (under), on the other hand, displays a list of the chemical agents.
The chemical agents that may be employed by terrorists range from those employed in wartimes to toxic chemical agents commonly used in the industry sector. The criteria required to draw up a possible list of chemical agents must take the following aspects into account:
- chemical agents that are already known because they have been used in wartimes.
- ascertained availability by terrorist groups.
- chemical agents capable of provoking a high mortality and morbility rate.
- agents capable of provoking social panic and upheaval.
- agents requiring a special response by public healthcare.
Table 2 lists the most probable chemical agents.
Tab2:
Possible chemical agents that may be employed for terrorist purpose:
· nerve agents,
· tabun (ethyl N,N-dimethylphosphoramidocyanidate),
· sarin (isopropyl methylphosphanofluoridate),
· soman (pinacolyl methyl phosphonofluoridate),
· GF (cyclohexylmethylphosphonofluoridate),
· VX (o-ethyl-[S]-[2-diisopropylaminoethyl]-methylphosphonothiolate);
· blood agents,
· hydrogen cyanide,
· cyanogen chloride,
· blister agents,
· lewisite (an aliphatic arsenic compound, 2-chlorovinyldichloroarsine),
· nitrogen and sulphur mustards,
· phosgene oxime,
· heavy metals,
· arsenic,
· lead,
· mercury,
· volatile toxins,
· benzene,
· chloroform,
· trihalomethanes,
· pulmonary agents,
· phosgene,
· chlorine,
· vinyl chloride,
· incapacitating agents,
· BZ (3-quinuclidinyl benzilate),
· pesticides, persistent and non-persistent,
· dioxins, furans, and polychlorinated biphenyls (PCBs),
· explosive nitro compounds and oxidizers,
· ammonium nitrate combined with fuel oil,
· flammable industrial gases and liquids,
· gasoline,
· propane,
· poisonous industrial gases, liquids, and solids,
· cyanides,
· nitriles and
· corrosive industrial acids and bases,
· nitric acid,
· sulphuric acid.
Box 1 Preparation for and Prevention of Bioterrorism
· Being prepared at a public healthcare level and ensuring that the agencies that operate at a local, regional and national level maintain the ability to react in a coordinated manner. Drawing up intervention guidelines and protocols in order not to be unprepared when faced with emergency situations.
· Establishing information channels (such as e-mail, information to be consulted on the Internet, dedicated telephone lines for information to the public and to medical practitioners), to improve the possibility of monitoring and diagnosing the diseases that may be deliberately spread through terrorist attacks. Holding training courses for public healthcare medical staff.
· Circulating standard and public healthcare behaviour guidelines on preparation plans for biological and chemical terrorism at a regional and national level.
Box 2 Diagnosis and Surveillance of Diseases that may be Deliberately Spread
-Strengthen local, regional and national surveillance systems for diseases and episodes resulting from pathogenic agents and chemical substances included in the CDC list mentioned above.
-Develop new algorithms and statistical methods to search for medical databases in real time, so as to be able to correctly interpret suspect events.
- Establish criteria for the identification of suspect clusters of human or animal diseases.
- Diagnosis and characterisation of chemical and biological agents.
-Set up a cooperation network at a laboratory level, connecting base laboratories to those specialising in the identification of particularly significant biological agents.
-Set up regional chemical laboratories that can supply diagnoses during attacks with chemical agents.
- Set up a rapid reaction and advanced laboratory technologies within the most important national institutions (ISS in Italy) to diagnose biological agents as quickly as possible and be able to carry out a quick molecular characterisation of biological agents belonging to the group.
Box 3 Response to Bioterrorism
· Assist the local and national facilities with respect to the response to be implemented in the event of a concealed or open terrorist attack, or in the event of the development of an epidemic that may be of an intentional nature.
· Ensure that the task force that has been organised and put in charge of the operations in response to a bioterrorist attack, from a technical, scientific and organisational point of view, is in a position to rapidly assist healthcare operators, safety agents and civil defence staff in the location in which an attack may be carried out.
· Prepare national supplies of antibiotics, vaccines and antidotes to be employed in the event of a terrorist attack using biological and chemical agents.
· Set up a network of contacts and connections to improve communications in the event of a local, regional or national emergency.
· Realise a communication plan for the public, containing healthcare information during suspected, threatened or implemented bioterrorist attacks.
· Create a website containing information relating to the preparation and training for and the management of emergencies for medical practitioners and other healthcare and emergency operators.
It is of the utmost importance that medical practitioners are able to detect, diagnose and notify diseases that may have been deliberately caused by bioterrorist actions. Early diagnosis and notification will make it possible to adopt as quickly as possible all the measures aimed at prevention and treatment of the cases, and at controlling possible epidemics.
The chief diseases that medical practitioners are to be aware of are:
Anthrax
Anthrax is an acute infection caused by the Bacillus anthracis. The disease most frequently affects sheep, goats and livestock, ingesting spores through contaminated soil. Human beings are infected through cutaneous contact, ingestion or inhalation of spores of B. anthracis transmitted by infected animals or animal products. There is no person-to-person transmission. The anthrax infection may develop in three different forms: pulmonary, cutaneous and gastrointestinal. Among these forms, only the pulmonary form is associated with bioterrorism through the inhalation of atomised spores.
The clinical features of each form are the following:
Pulmonary Form:
- Non-specific flu-like prodromes following inhalation of the spores.
- Possible brief transitory improvement.
- 2-4 days after the initial symptoms, sudden onset of respiratory insufficiency and collapse, possibly accompanied by pulmonary edema and widening of the mediastinum, visible through thoracic X-rays, suggesting mediastinal lymphadenopathy and haemorrhagic mediastinitis.
-Gram-positive bacilli resulting through blood culture, 2-3 days after disease onset.
- Curable during the initial prodromic phase. The mortality rate remains extremely high, despite the antibiotic treatment, if this has been started after the appearance of the respiratory symptoms.
Cutaneous Form (see tab. II)
-Cutaneous lesions following direct contact with spores or bacilli.
-These normally appear on forearms, hands and head.
- Localised itching, followed by papulae developing into vesicles, which become black depressed eschars within 2-6 days.
-Usually non-lethal if treated with antibiotics
Gastrointestinal Form
- Abdominal pain, nausea, vomiting and fever, following ingestion of contaminated meat.
- Bloody diarrhoea, hematemesis.
- Gram-positive bacilli resulting from blood culture, usually after two-three days from onset.
- If it progresses to toxaemia and sepsis it becomes fatal.
Transmission modalities for anthrax are:
- Inhalation of spores.
- Cutaneous contact with spores or with material polluted by spores.
- Ingestion of contaminated food.
The incubation period following exposure to the B. anthracis ranges from 1 to 8 weeks, depending on the transmission route and the dose:
- 2-60 days in the event of pulmonary exposure.
- 1-7 days after cutaneous exposure.
- 1-7 days after ingestion.
The possibility of person-to-person airborne transmission is not possible (or at least it is highly unlikely). Direct contact with cutaneous lesions may involve a contagion risk of developing the cutaneous form.
Infection Control and Patient Management
Symptomatic patients with suspected of confirmed anthrax are to be managed according to specific guidelines: - Caution. Standard precautions need to be taken in treating patients with anthrax. The use of gloves is imperative in taking care of these patients. It is necessary to accurately wash, disinfect and sterilise medical equipment, clothes worn and the surrounding environment. - No need for isolation. This is not required since transmission is not airborne. Only cutaneous lesions may be contagious.
Guidelines on the Behaviour to be Adopted in the Event of Suspect Mail The CDC recommends, in the event of suspect mail, the following behaviour: do not open, or shake the contents, cover the suspect package or envelope with other items, leave the room, inform the police, take off your clothes and put them in a plastic bag, make a note of the people who may have come in contact with the suspect mail, accurately wash hands and body.
Preventive Measures
A vaccine exists in the USA: this is given to soldiers and to those who are exposed for professional reasons. The vaccine is administered in six doses, the first two at one week’s distance, the third 4 weeks after the first, the fourth, fifth and sixth respectively six months, one year and one and a half years after the first.
Prophylaxis
The prophylaxis with antibiotics must be started after exposure to anthrax has been confirmed. It is carried out with cyprofloxacine 500 mg twice a day and, for children the daily dose must be of 20-30 mg/kg bodyweight divided into two doses. If fluoroquinolones are not available or if there are contraindications, doxycicline 100 mg should be administered twice a day (in children the daily amount will be 5 mg/kg bodyweight to be divided into two doses).
Prophylaxis must continue until exposure to anthrax has been excluded. If exposure is confirmed, the prophylaxis must continue for two months. In addition to prophylaxis, post-exposure vaccine is also indicated, with inactivated, acellular vaccine. Post-exposure vaccination is administered in three doses, immediately, 2 and 4 weeks after exposure. If the person exposed is immunised through the vaccine, the duration of the antibiotic treatment may be reduced to 4-6 weeks.
Botulism
The Clostridium botulinum is a bacterium that produces a powerful neurotoxin inhibiting the release of acetylcholine into nerve endings, thus causing flaccid paralyses. The C.botulinum produces spores which can be found worldwide in the soil and in the marine sediment. Intoxication takes place through the ingestion of contaminated food, which cause gastrointestinal symptoms, but a form of botulism caused by inhalation is also possible. As a bioterrorist agent, botulism can be transmitted both in the inhalation form and in the gastrointestinal form, bringing about similar symptoms:
- Symmetric cranial neuropathies (deglutition and talking difficulties, trismus and lid ptosis).
- Blurred vision and diplopia.
- Symmetric descending weakness (paralysis of arms to start with, followed by that of the breathing muscles, and hence by that of the lower limbs).
- Paralysis of the breathing muscles, obstruction of upper airways owing to paralysis of the glottis.
- No sensorial deficit.
- No fever.
Transmission route:
- Ingestion of food containing the botulin toxin.
- Atomisation of the botulin toxin.
- Person-to person transmission of botulism cannot take place.
Incubation Period
The neurological symptoms of botulism due to food ingestion start 12-36 hours after ingestion. The neurological symptoms of botulism due to inhalation start 24-72 hours after exposure.
Preventive Measures
The American Department of Defence has arranged for a vaccine that is administered in three doses (0, 2 and 12 months).
Patient Management Procedures
For the management of patients affected by botulism, standard precautions are to be taken; isolation is not required since the disease does not involve person-to-person transmission. The principles relating to hygiene, disinfection and sterilisation of equipment, of medical tools and of the environment must also be applied in these cases.
Post-exposure
Even a single case of suspected botulism must immediately suggest the possibility of an epidemic associated to contaminated food. It is therefore necessary to identify the food that has caused the intoxication. Exposed patients must be hospitalised and monitored. Since botulin toxin contamination does not involve the risk of a cutaneous exposure or a risk associated with re-inhalation, patient decontamination is not necessary. A trivalent anti-botulin vaccine produced from horse serum exists. In the USA it has been observed that it produces a<9% percentage of hypersensitivity reactions.
Laboratory Confirmation
Laboratory test have a limited value in the diagnosis of botulism. The toxin can be identified from the serum, from faeces samples and from gastric secretions.
Plague
Plague is a bacterial disease caused by a Gram-negative bacillus called Yersinia pestis, which is usually caused by infected fleas. The infection involves the lymphatic system and the blood (bubonic and septicemic plague). A bioterrorist-induced epidemic is most likely to be airborne, by provoking the pulmonary variant of this disease. The clinical features of pulmonary plague are:
- Fever, cough, thoracic pain.
- Haemoptysis.
- Watery mucopurulent excretion.
- X-ray evidence of bronchopneumonia.
Transmission Modality
Plague is normally transmitted by an infected rodent to man, through infected fleas. There is the possibility for the disease to spread through person-to-person transmission. Epidemics caused by bioterrorism could be caused through atomised dispersion.
Incubation Period
The incubation period for plague is of 1-3 days in the pulmonary variant and of 2-8 days if transmitted by fleas through mice.
Preventive Measures
An inactivated vaccine exists for bubonic plague, but its effectiveness has not been tested for pulmonary plague. Vaccination requires multiple doses taken at various weeks’ distance. Its use is not recommended for the population at large. Post-exposure vaccination is of no practical use. Patients affected by pulmonary plague may display a cough producing infecting droplets. The use of protective masks is recommended for who takes care of such patients.
Patient Management
Symptomatic patients with suspect or confirmed plague must be managed according to set guidelines. Medical and nursing staff must wear surgical masks at least until the patient has completed 72 hours’ antibiotic therapy. Affected patients are to be isolated or placed in single rooms. Should this not be possible (in the unfortunate case of a large-scale epidemic), patients with a similar symptom cohort and presumably the same diagnosis should be placed together. Patient transfer should be avoided but, should it prove necessary, patients are to wear masks to minimise the release of infecting droplets through coughing or breathing.
Decontamination
Patients must be instructed to take off contaminated clothes and place them in plastic bags (which will be subsequently labelled and stored by specially appointed staff), to handle contaminated clothes as little as possible and to take an accurate hygienic shower. The staff on duty will have to wear special barriers when coming in contact with patients’ clothes or other articles. The environment will have to be treated with sporicidal or germicidal agents or with 0.5% sodium hypochlorite.
Prophylaxis
Post-exposure prophylaxis recommended by the CDC prescribes, as first choice, doxycicline 100 mg twice a day, followed by cyprofloxacine 500 mg twice a day. The prophylaxis must be continued for 7 days after an actual or supposed exposure to Y.pestis.
Therapy
The drug to be chosen is streptomycin. As an alternative, gentamycin.
Smallpox
Eradication of smallpox has represented one of the greatest successes of the World Health Organisation.
Smallpox represents a bioterrorist threat, in that it causes a severe disease in a population that is no longer vaccinated and because of the fact that it is an airborne disease. Even a single case must represent an emergency for public health.
Clinical Features
12-14 days after the infection, the patient develops fever and head and back pain, as well as prostration. 2-3 days later an exanthema develops on the face and it propagates to the extremities. The primary papula lesion, develops into a vesicle and hence into a pustule. The patient suffers from fever for the whole duration of the rash, while the pustules widen and propagate to the extremities, including hand palms and feet plants, which does not happen with chickenpox, a disease with which it might be confused during the initial stages. In smallpox all cutaneous lesions develop at the same time: therefore there will only be papulae, only vesicles or only pustules, and not a mixed exanthema (in Italian: manifestazioni “a cielo stellato”), as for chickenpox. In addition, chickenpox lesions are more superficial. In 5-10% of patients, smallpox has a malignant course, which proves almost always fatal after 5-7 days.
Transmission Modality
Smallpox is a viral infection typical of human beings. In order to survive, the virus is to be transferred from person to person, thus continuing the infection chain, and is spread by inhalation of breath droplets or atomisation. The disease may be also transmitted through contact with lesions and skin secretions.
Vaccine
In anticipation of a use of smallpox as a biological weapon, a certain supply of vaccine exists in the USA. Vaccination is also effective after exposure. The problem relates to the difficulties in procuring the vaccine, especially in Europe. Vaccination against smallpox does not grant a life-long immunity. People vaccinated in the past need not be protected at the moment. Vaccination is associated with a certain adverse reactions risk. The two chief complications are post-vaccine encephalitis and the diseases induced by the vaccine virus. Post-vaccine encephalitis arises in 3 cases out of a million. The second complication takes place in immunodepressed people. What happens, in fact, is that the vaccine virus continues to grow and, unless these patients are treated with specific immunoglobulins, they may not recover. Routine vaccination is only recommended for staff working in the laboratories that still store the vaccine. Mass vaccination is not conjecturable, first of all because the current vaccine may give rise to complications, since it is an old-generation type, and secondly because there are insufficient supplies for large-scale employment.
Patient Management
Patients with suspected or confirmed smallpox must be placed in strict isolation in negative pressure rooms. The room should be given 6-12 airings per hour. Air ventilation outlets should be protected by specially devised filters. The room door must remain closed.
Where does the Bioterrorist Threat come from?
When the WHO considered the disease had been eradicated, it decided that the various virus strains be stored for precautionary and study reasons for a certain number of years in two laboratories: one in the Atlanta CDC, and one in the Virology and Biotechnology Research Centre in Koltsovo, Novosibirsk region, in Russia. With the 1996 resolution, the World Health Assembly decided to postpone the destruction of the viruses until June 1999. The date for the destruction of the viruses was subsequently again postponed to the year 2002. The destruction of the viruses may prove crucial to prevent a bioterrorist threat, but we cannot in theory exclude that States that support Islamic fundamentalism and terrorism, and the terrorists themselves have this biological weapon available, thanks to an illegal trade which could have taken place, for instance, at the time of the collapse of the ex-USSR regime or as a result of some countries not having delivered, at the time it was requested, smallpox strains to the two WHO reference laboratories.
Walter Pasini
Direttore del Centro Collaboratore dell’Organizzazione Mondiale della Sanità per la Medicina del Turismo
