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Pr. Didier Raoult: How to cope with new contagious diseases?

Read the facsimile of the orginal document by Pr. Raoult

Introduction:

Until the 20th century, infectious diseases and epidemics played a major role in human history, representing the major cause of mortality and provoking epidemics that changed the course of history, from the Plague of Athens that decimated the Athenian population during the Peloponnesian War, to the Black Death that in the 15th century killed 30% of the European population, then typhus during the Napoleonic Russian Campaign which was responsible for about half of the deaths in the Russian retreat, Spanish flu which in 1918 killed as many as in the World War I (20 million deaths), to louse-borne diseases which, during the war and then the Bolshevik Revolution in Russia, caused 3 million deaths.

Alongside these major epidemics, infectious diseases have found new opportunities in the changes in our ecosystem and have particularly developed in hospitals in the form of nosocomial infections. Hygiene, the increase in the standard of living in the most developed countries, combined with vaccination and then, from the World War II onwards, the use of anti-infectives, have led to a decrease in infectious diseases and have been correlated with a spectacular increase in life expectancy. In 1995, infectious diseases were responsible for only 30% of global mortality worldwide. However, this figure in fact conceals the fact that they remain the leading cause of shortened life expectancy because they affect young and old alike, unlike cancer or cardiovascular infections.

The disappearance of the major infectious diseases identified in the course of the 20th century (decline in tuberculosis, disappearance of smallpox, almost disappearance of poliomyelitis, diphtheria) may have suggested that the problem was residual. However, epidemics are chaotic phenomena, poorly predictable and poorly controllable. A radical change in the public mind occurred with the emergence of AIDS in the 1980s, when a disease of ever-increasing magnitude appeared, spread extremely rapidly throughout the world and constituted the paradigm of the new, totally unforeseen epidemic. Since that time, and thanks to the intervention in the United States of America of the Institute of Medicine, which defined the concept of emerging diseases in 1992, a mobilization of the scientific community, essentially American but also international, has taken place around the problem of emerging infectious diseases, which has made it possible in some 20 years to identify 200 new pathogenic microorganisms, which are either old but recently identified thanks to technical progress, or entirely new. Five major problems have been identified:

1- Major epidemics that were thought to be forgotten, reappear during social disasters, particularly civil wars, around the world. Thus, in the last 10 years of the 20th century, the global incidence of the plague increased (particularly in Madagascar); cholera, which had long been limited to Asia and Europe, has now spread to the African continent in the 1970s and to the American continent in the 1990s with an ever-increasing number of cases and deaths. Diphtheria (although well controlled by vaccination) exploded in the 1990s in the former USSR after the decline in vaccination, as well as in Algeria. Finally, louse-borne diseases have reappeared; the largest Typhus epidemic since World War II began in Burundi, Rwanda and Congo and is still evolving, and trench fever has taken hold in urban areas in developed countries, including France (Paris, Lyon and Marseille). Thus, we have seen the return of major infectious diseases, reflecting a decline in social control and a decrease in vigilance against these pathogens. The means of controlling these diseases are, however, extremely simple, based on the quality of social services, vaccination and the national hygiene management policy.

2- Nosocomial infections develop in the hospital ecosystem. In this area, France is in a particularly bad position compared to other major nations. It is estimated that 500,000 people suffer from nosocomial infections per year, 10,000 of whom die.

3- The explosion of the resistance of microorganisms to antimicrobials is a cause for concern. Thus, resistances have emerged, even for extremely common microorganisms, with a race between human pharmaceutical ingenuity and microorganisms that has left no definitive winner. Staphylococcus has become resistant to Sulfonamides, Penicillin, Tetracyclines, Anti-staphylococcal Penicillins and now Vancomycin, as the pharmaceutical industry has discovered. Pseudomonas aeruginosa have also become resistant in a number of cases to all antibiotics except Colimycin. Pneumococci become resistant to the first line antibiotics, Penicillin and Macrolides. These microorganisms are common infectious agents that have been fully controlled in recent years. Finally, the tuberculosis bacillus shows an increasing level of resistance in Eastern European countries. The rapid increase in resistance poses very worrying problems. It is the result of a balance between microorganisms and antibiotic prescription. The latter undoubtedly constitutes a selection pressure that favours the emergence of resistant microorganisms. These microorganisms are then eventually transmitted from patient to patient in an epidemic manner, either directly or, as in the case of Staphylococcus aureus, through caregivers. France is the country with the most antibiotic prescriptions and the highest levels of antibiotic resistance.

4- The fourth problem is the use of microorganisms as agents of bioterrorism. The first use of microorganisms as a warfare agent is extremely ancient, dating back to the use in 1347 in Caffa by the Mongols of pestiferous corpses, thrown over the walls, to infect the population defending the besieged city. Since then, many microorganisms have been proposed and have been used as biological weapons. These include, among others, the bacteria of typhus, brucellosis, tularaemia, anthrax and plague. The 1972 Non-Proliferation Treaty, signed by all countries, gave hope that the use of these microorganisms as a weapon of war could be eliminated. In fact, it was found in 1979 that the Russians had continued their studies on anthrax during an anthrax epidemic in Russia that resulted in about 100 deaths in a city that included a military laboratory. Autopsies of these patients who died in charts of pneumonia with brain haemorrhage revealed the anthrax bacillus and the fact was recognized by Boris Yeltsin in 1992. In addition, a few cases of smallpox have occurred among cruise passengers travelling on the Aral Sea, in front of a Russian military laboratory. These cases of smallpox were extremely serious, haemorrhagic, and resulted in the death of vaccinated subjects, without these patients having had direct contact with a smallpox subject. This suggests that they were victims of an aerosol spray from the military laboratory in question and that the smallpox virus was particularly virulent. Subsequently, bioterrorism originated with the Aum sect in Japan. It used sarin gas in the subway and made attempts to use anthrax, Q fever and botulinum toxin. The Gulf War led to the identification of anthrax stockpiles in Iraq. Recent information may have shown that the Al-Qaeda terrorist network was proposing to use a number of infectious agents as a source of terrorism. Finally, a few cases of anthrax that followed postal consignments occurred in the United States in 2001 and the discovery of a stockpile of ricin toxin in England in 2003 made this risk a reality. The threat of the use of bioterrorist agents is likely because the cost of producing biological weapons is 2000 times less than that of conventional weapons of comparable effectiveness.

5- The fifth threat is emerging viruses. The 1970s saw the emergence of haemorrhagic fever viruses in Africa and South America (Lassa, Ebola, Machupo). Epidemics have so far been limited but have raised the problem of handling highly pathogenic agents, possibly contaminated by aerosols in the laboratory and which, with sudden and frequent mortality, would pose a threat equivalent to that of the Black Death of the Middle Ages if human-to-human aerosol transmission became natural. The 1980s were the years of AIDS and the 1990s were the years of hepatitis C. The current risk of the appearance of mutants of respiratory viruses, particularly the flu, is the most fearsome phenomenon. A new influenza mutant appeared in 1999 in Hong Kong. This virus of avian origin, which is frequently fatal, was quickly brought under control, but the next influenza mutant may not be. The risk of epidemics from respiratory diseases is extremely high due to the dense human population. Currently, more than 1.6 billion people live in cities, including 24 megacities with more than 10 million inhabitants, most of which are now in countries with low economic levels. Between 500 million and 1 billion air travel trips will take place in all corners of the planet during 2003, and the mutualisation of a virus transmissible by the respiratory route will be extremely rapid. This type of event, the sudden mutation and then introduction of a virus of animal origin into the human world, are rare, chaotic events but can have extremely rapid and dangerous consequences. Only the sustainable establishment of research and surveillance centres in tropical countries will enable the early detection of these new agents.

Our preparation for these chaotic events is weak for several reasons. First of all, because the era does not lend itself to the prediction of catastrophic events (Cassandra is always ridiculous!). The social needs relayed by the press are immediate needs; they respond to spontaneous fears that are quickly dispelled by other fears or worries. Under these conditions, setting up a system that makes it possible to avoid the dramatic consequences of improbable and long-term events is extremely difficult. It is even likely that this would raise extremely negative comments in the press denouncing catastrophism, paranoia and even wastefulness. Yet the cost of emergency response is far greater than the cost of prevention. For example, the cost of preventing infection with the new variant of Creutzfeldt-Jakob disease (mad cow disease) in hospitals, relative to the public health benefit, is improbably high. Thus, a long-term monitoring policy requires the political courage to invest in phenomena that are not very interesting to the media, that are sometimes even worrying for the population (construction of P4, P3) and that require a little sustainability in the choices.

Moreover, contagious diseases contradict the spectacular individualistic evolution of our society in recent years. Indeed, the management of infectious diseases can lead to the questioning of individual freedom. This is the case of the isolation necessary to avoid contamination when patients are contagious, it is the case of the compulsory declaration of diseases and it is the case of compulsory vaccination in the context of contagious diseases. It may also be the justification for compulsory care for other contagious diseases. Since humans constitute a single species, individual human behaviour can have an impact on the health of the entire population. For instance, it was possible to identify a Guinean student who imported cholera into Black Africa from the USSR and secondarily caused millions of deaths. Thus, the individual freedom of each person and personal choices can contradict the needs of society in a very tangible way.

The widening development gap between the richest and poorest countries gives hope to the richest that the diseases of the poorest will remain confined to the Third World. In the case of contagious diseases, this is not likely. The human species is unique, microorganisms move around and any emergence of a new pathogen in any country of the world will allow it to spread rapidly without any control at borders. This means that the richest countries (even in the most selfish way) have to be very careful about the health in terms of contagious diseases of the poorest countries. This is all the more true since the progressive constitution of megacities, when not associated with sanitary development allowing a minimum of hygiene, will give, through population growth and promiscuity, the opportunity for new pathogens to develop extremely rapidly. The conditions in these megacities are such that extremely dangerous microorganisms can appear.

In the perspective of the fight against infectious diseases, a very worrying phenomenon is emerging: the industry invested in the fight against infectious diseases is emerging very quickly. Indeed, internationally, companies such as Novartis, GlaxoSmithKline, Bristol Meyers Squibb, Eli-Lilly and Laroche-Hoffman are either cutting back on their investment or leaving the field of antibiotics altogether. The same situation can be observed with regard to vaccinations. The number of operators likely to create vaccines has now become extremely low. It is likely that we will soon arrive at the paradox that Science will propose original therapeutic vaccine strategies that cannot be marketed for lack of operators. This is linked to the increasingly spectacular cost of development, which does not allow a satisfactory return on investment. The State will therefore have a considerable role in the future as the market is disengaging from the battle against infectious diseases.

The new contagious diseases:

The emergence of new rapidly fatal contagious diseases was observed in the 1970s with the appearance of haemorrhagic fever viruses from Africa (Ebola, Lassa). The emotion aroused at the time, which had justified the construction of a few rooms in depression, quickly subsided and the problem remained neglected.

There is always a considerable risk of the emergence of new pathogens which, given the frequency of travel and globalisation, would be rapidly mutualised worldwide. The preferred areas in which the appearance of these infections can be feared are the densely populated areas, particularly the Third World megacities in Africa, South America and especially Asia. Thus, the setting up of observatories to collect data in the different corners of the world by developed countries is becoming an essential element of Public Health: this is one of the elements recommended by the WHO and this is what the United States is doing in Lima, Cairo, Nairobi and Bangkok. Among the French-speaking countries, there are few or no settlements and this role has historically fallen to us. This monitoring is less and less carried out due to the dispersal of the resources of the main actors (French Defence Health Service, ANRS-The French National Agency for AIDS Research, IRD-The French Research Institute for Development, and the Institut Pasteur) and the fact that the French Defence Health Service is currently in considerable decline due to the professionalisation of the army.

There is an undeniable danger of a new influenza virus or mutant equivalent to the airborne Spanish flu, which would spread extremely rapidly through travel and could lead to an epidemic with incalculable consequences of several million deaths. Recent respiratory viral episodes have been aborted (Nipah virus, Equine Paramyxovirus, new avian influenza mutant from Hong Kong). However, the risk of global spread is still great. Preparedness for such a possibility needs to be strengthened.

Firstly, safe air travel capacity is low or non-existent in almost all countries. The decision taken in such a situation would probably be to stop transporting patients and let treatment take place on site. This raises the question of setting up hospitals on site in cooperation, with a sufficiently high technical and scientific level to provide treatment on site for our nationals, including possibly military personnel. The airport monitoring system must be developed. An infirmary allowing isolation must be set up at international airports. Specialised ambulances for the isolation and transport of contagious patients must be equipped in major international airports.

Once they arrive, suspect patients must be quarantined; the country’s legislative arsenal does not currently allow this, any more than it would for someone who has self-inoculated with smallpox. It only allows it with the patient’s consent. This problem must be the subject of a profound debate in France so that, when someone endangers the population, it is possible to force them to be isolated and receive care.

Once we get to the hospitals, the situation has to be planned. The first step is to be able to identify suspicious patients in all emergency departments and then to refer them to services where they can be cared for. Gloves and masks should be widely worn by caregivers and patients with severe pneumonia. In order to be able to manage a highly contagious patient in a unit, he or she must be isolated, the equipment for medical personnel must be available to avoid contagion (coveralls, mask) and the patient must be able to be admitted to a room in depression. In such chambers, the air is captured inside the chamber by a flow system going from the outside to the inside; what comes out of the chamber is filtered, as an absolute filter, to avoid environmental contamination (P2 or P3). For the most serious patients, it is necessary to have a few beds in intensive care. There is also the problem of sampling circuits and paraclinical examinations. For paraclinical examinations, at least one quality portable radio must be available, which will be left in the unit in question. In addition, it must be possible to handle biological examinations and, first of all, those intended to allow the search for pathogenic P3 microorganisms. Until the microorganism in question has been identified, it is not known whether it is necessary to grow it in P4 and therefore P3 should be used until an atypical effect occurs. Associated biotox reference centres in at-risk cities should be involved in the initial isolation strategy. Suspect viruses should be sent to the Lyon P4.

In addition, it must be possible to process basic samples (count formula, ionogram) under safe conditions, and samples from a suspect patient cannot be injected into the general circuit. This means that within the P3 laboratory, the means must be organised to make the minimum assessments for vital constants on low-volume devices (hemogram, coagulation, ionogram).

There is only one room in depression in France at the moment in the hospital in Lyon and no unit in depression. Requests for equipment from La Pitié (Professor BRICAIRE) remained unanswered until 2003. The only room in Bichat is no longer functional. Projects are underway, particularly in Montpellier. The setting up of a possible processing of samples is being done in Lyon in a P2 laboratory. It is the only team with experience in France at this level. It is striking to note the experience of other countries around. Recently, I had the opportunity to visit the dedicated structure in Milan, in the STACCO hospital. The Infectious Diseases Department has 3 units of 100 beds each, where each of the rooms is in depression and makes it possible to work instantly on 100 contagious patients. In addition, a building is under construction, the financing of which was decided in 2002 within the specific framework of bioterrorism (for which there will be 2 centres, in Rome and Milan), which will have 10 to 20 rooms in a complete P3 level complex including, in addition, a laboratory, a block and a morgue to be able to take histological samples. This type of development will make it possible to deal with a possible catastrophic situation of an extremely contagious epidemic by protecting the population and the medical staff.

In sum, the risk of the appearance of a new, highly contagious pathogen, particularly via the respiratory tract, is clear; it is a rare and chaotic event, and it is essential to prepare for it in advance to try to avoid a massive spread that could have considerable consequences. The example of the Black Death in the Middle Ages, which destroyed a third of the European population and killed half of the population in Marseille in 1720, or the Spanish flu, which killed more than 20 million people in 1918, must be kept in mind. In order to organise things, whole services must be set up in Paris, Lyon and Marseille, to begin with, which can be transformed into a service for receiving highly contagious patients. These services must be made up of about twenty beds, with rooms that can all be turned into a room in depression. This service must be associated with a laboratory which could be on a different site, in the same town, of the P3 type, in which routine biological examinations and microbiological tests can be carried out. Finally, radiology capabilities and probably a mini operating theatre must also be set up in this structure so that we can live in medical self-sufficiency.

Recommendations:

– Equip the P3 laboratories of the associated biotox laboratories in Paris, Lyon and Marseille with mini automatons to perform routine P3 biology for patients suspected of being highly contagious.

– Designate 3 reference centres for the isolation and characterisation of highly infectious pathogens, Paris, Lyon and Marseille.

– Plan the construction in Paris, Lyon and Marseille, to begin with, of complete Infectious Diseases units entirely in P3, including a few intensive care beds, a mini operating theatre, radiological capacities and allowing the unit to be completely isolated in terms of infectious risks.

– Equip international airports with infirmaries allowing the isolation of suspect patients (in depression).

– Prepare an isolation circuit from airports and train stations to one of the 3 identified centres (Paris, Lyon, Marseille) in conditions that prevent the spread of microorganisms, using specialized ambulances.

– Set up circuits for sending suspicious samples.

– Conducting exercises and simulations.

– Develop the use of masks for caregivers and patients with severe lung disease.