School of Medicine, University of Birmingham, Birmingham B15 2TT, UK
Abstract
The late Paul Garrod, in whose honour this lecture is named, was the right man at the right time. He seized the opportunities offered by the dawning of the chemotherapeutic era with vigour and enthusiasm and was a formidable link between the traditional laboratory-based bacteriologist and the more clinically orientated modern medical microbiologist. Professor Garrod was a founder member of the British Society for Antimicrobial Chemotherapy and I had the privilege of meeting him on many occasions. He would have relished the many challenges facing today's microbiologists, infectious disease physicians and public health experts. These will have major implications for antimicrobial chemotherapy in the twenty-first century. The emergence and prevalence of infectious diseases, and the necessity for discovering therapies to treat them, are influenced by many factors. In this lecture I will discuss four which could have a major influence on infectious diseases in the twenty-first centuryglobal warming, biological warfare/terrorism, the dissemination of infections, including those caused by resistant pathogens, by travellers and certain untreatable zoonotic diseases.
Biological warfare/terrorism
The ideal biological weapon would be: (i) capable of being produced in large quantities; (ii) relatively stable over a range of temperatures; (iii) capable of being sprayed as an aerosol; (iv) difficult to identify quickly e.g. a toxin. Furthermore, if a microorganism is to be used, it should be resistant to readily available chemotherapeutic agents and the infection produced should have a high mortality, e.g. anthrax. Anthrax and plague have been predicted to cause the highest number of dead and incapacitated, as well as the greatest downwind spread according to the WHO Group of Consultants in 1970.1 Finally, the target population should not be protected by immunization.
Several pathogenic micro-organisms have the potential to be used as biological weapons. Chief amongst these are Bacillus anthracis, the smallpox virus and Clostridium botulinum.
Anthrax is an especially favoured biological weapon. Untreated, the mortality of anthrax exceeds 80%. A few kilograms of the organism can kill as many people as a Hiroshima-sized nuclear weapon.2 It has been claimed3 that, in 1995, Iraq had a large enough store of anthrax spores (8000 L at a concentration of 109/mL) to kill all the inhabitants of the earth 2500 times over! Inglesby4 constructed a theoretical model, based on a city on the Eastern seaboard of the USA with a population of 2 million, that envisaged a truck releasing powdered anthrax spores over an area one-third of a mile wide alongside a sports stadium containing 74000 spectators. He postulated that 20000 persons within the city would be infected, of whom 4000 would die, most in the first 10 days, and that 250000 individuals in the stadium and in the immediate vicinity would need to receive prophylactic antibiotics. The challenges that such a scenario would create would be extraordinary.
Allegedly there have been experiments into the devastating effect on animal life in Northern Canada of botulinum toxin sprayed from an aircraft, indicating that inhalation of the toxin can cause botulism.5 Because of the classified nature of the experiment, details of this study are not available. This bacterium would, therefore, be extremely suitable as a biological weapon.
Although smallpox was eradicated from the world in the late 1970s, there are still stocks of the virus held in two laboratories, one in the USA and the other in Russia. Furthermore, it is possible (and, perhaps, probable) that illicit stocks of the virus have also survived and could be used as biological weapons. D. A. Henderson, who led the WHO programme for the eradication of smallpox, has stated6 that, Smallpox is rated amongst the most dangerous of all potential biological weapons, with far-reaching ramifications. One can only speculate on the probable rapidity of spread of the virus in a population where no one younger than 25 years of age has ever been vaccinated and older persons have little remaining residual immunity. Smallpox is transmitted by the airborne route and in an aerosol suspension can be disseminated widely. The expected case fatality would be around 30%. The vast majority of the population has no immunity against the infection and there is little available vaccine and no effective treatment. Fifteen million doses of the freeze-dried vaccine are stored by the Centers for Disease Control and Prevention in Atlanta, GA, USA. However, it has been estimated that 40 million doses would be required to respond to a terrorist attack in the USA. There is such a degree of concern in the USA about the possibility of bioterrorism with the smallpox virus that experiments are in progress to determine the efficacy of 10-fold dilutions of smallpox vaccine.7
Other microorganisms that have the potential of being used as biological weapons include Coxiella burnetii, Francisella tularensis, Yersinia pestis, Brucella suis and the haemorrhagic fever viruses.
It is probable that bacteria employed as biological weapons will have multiple antibiotic-resistance patterns.
Travel and the dissemination of infection
The major epidemics that have afflicted the human race have all been transmitted internationally by travellers. Plague, which caused vast numbers of deaths throughout Europe between the fourteenth and eighteenth centuries and syphilis, believed to have originally been imported into Europe from the New World by Spanish sailors, are examples. Plague is probably one of the oldest afflictions of the human race. Originating in India it reached the Crimea in 1347 and was imported by ship-borne rats into Venice and Genoa from where it was carried by travellers to northern European countries.8
Syphilis was imported into Europe by the Spanish conquistadores returning from the New World.8 It first appeared in Barcelona in 1493 (hence it was originally termed the Spanish disease) and spread to France and Italy and then to Germany where it was known as the French Disease! The infection reached the British Isles in 1496. At about the same time, trans-Atlantic transmission of infection in the reverse direction occurred with measles that devastated a totally non-immune population of native American Indians. A recent example of an infection that crossed the Atlantic from east to west is West Nile encephalitis, a viral infection that caused an outbreak of encephalitis in New York in 1999.9 The route of spread from Africa to America is unknown although infected mosquitoes travelling in an aeroplane are a possibility. Dengue has crossed the Pacific Ocean to the Western shores of America. The infected mosquitoes were probably transported in motor car tyres being shipped for re-treading.10 The higher winter temperatures in California consequent of global warming (see below) probably allowed the mosquitoes to survive in what previously would have been a hostile environment.
There has been an exponential escalation in numbers of world travellers over the past 30 years. Travel has become an important route of transmission of antibiotic-resistant microorganisms. Examples include Mycobacterium tuberculosis, Streptococcus pneumoniae, Neisseria gonorrhoeae and methicillin-resistant Staphylococcus aureus (MRSA).
Probable transmission of multi-drug resistant (MDR) M. tuberculosis occurred during an airline flight.12 A patient suffering from infection with MDR M. tuberculosis flew from Honolulu to Chicago and then on to Baltimore. Six passengers on the flight in close proximity to the index case were found subsequently to have positive tuberculin skin tests, four with skin test conversions. Richard Wenzel11 discussed aircraft ventilation in the context of on-board transmission of infectious diseases. Aircraft cabin air is exchanged every three to four minutes; half of the air is fresh and half is re-circulated. The re-circulated air passes through high efficiency filters. Airflow is laminar from the top of the cabin to the floor. The opportunity for the transmission of infection via the air-conditioning system is therefore very limited and it seems most likely that direct face-to-face contact was the mode of transmission of tuberculosis in the episode described above.12
Penicillinase-producing (penicillin-resistant) gonococci were first detected in Liverpool, England in 1976, a port with sea routes to and from West Africa.13 These organisms became especially prevalent in the Phillipines, in other southeast Asian countries, especially Singapore and Thailand, and also in west Africa. Since that time they have been found in all countries of the world where they can pose major problems to public health. ß-Lactamase- producing gonococcci may also be resistant to non-ß-lactam antibiotics such as the tetracyclines and erythromycin.
Pneumococci resistant, or of decreased sensitivity, to penicillin were first identified in Papua New Guinea in 1967,14 and since that time they have spread throughout the world. In 1993, Soares and colleagues15 reported the transmission of a multi-resistant S. pneumoniae strain from Spain to Iceland and suggested that it had been imported by Icelandic families returning from holiday in Spain. Almost all the resistant organisms were of subgroup 6 and appeared suddenly over a 3 year period from 1989. Molecular analysis revealed that they were of serotype 6B and were indistinguishable from a similar serotype that had been prevalent in Spain during the previous decades.
A report in 1998 by Aires de Sousa and colleagues,16 using molecular fingerprinting techniques, described the spread of an MDR clone of MRSA from Brazil to Portugal, countries with regular air links. The study reported the abrupt appearance and extensive intra-hospital spread of the Brazilian epidemic MRSA clone in three Portuguese hospitals.
As aeroplanes become larger (and probably also faster) and flights become cheaper the number of world travellers will continue to escalate. The potential for the rapid transmission of infectious agents, including those that are resistant to antimicrobial agents, will also increase.
Global warming
The Intergovernmental Panel on Climate Change predicted in 199517 that there would be an increase of 1°C to 3.5°C in the average world temperature during the twenty-first century. The Panel noted that such a rate of climate change would be far greater than any alteration in the climate of the world since the advent of agriculture 10000 years ago.
In the absence of the natural greenhouse gas effect the average temperature of the world would be only 18°C, instead of the actual average world temperature of +15°C. The greenhouse effect is therefore essential for survival of the human race. The main greenhouse gases are CO2, CH4, N2O2 and members of the halocarbon and related families: chlorofluorocarbons (CFCs), hydrochlorofluorocarbons (HCFCs) and hydrofluorocarbons (HFCs). Ozone is also important. During the past 150 years, CO2 concentrations in the atmosphere have increased by 25% from fossil fuel burning, and methane levels have more than doubled as a result of coal mining and domestic waste. In addition, depletion of ozone in the stratosphere due to CFCs, which were only introduced in the 1930s, causes an increase in the amount of ultraviolet B radiation reaching the earth from the sun. These factors have contributed to an increase both in the overall canopy which keeps the earth warm, and also in the amount of heat reaching the earth from the sun. The result is a warmer planet.
What could the consequences of global warming be for infectious diseases, and therefore for chemotherapy? Possibly surprisingly, in view of the relatively minor predicted changes, the consequences of global warming would be dramatic.18 The following could occur, especially in countries with temperate climates: (i) warmer summers and milder winters; (ii) higher sea levels due, in part, to polar ice melting leading to flooding; and (iii) geographical migration of the insect vectors of infectious diseases.
As a result of these factors there would be alterations in the geographical range and incidence of vector-borne diseases such as malaria, and also in water-borne infections.19 In addition, new infections, particularly zoonotic diseases, would emerge.
Malaria has attracted particular interest in the context of global warming. Plasmodia have fairly precise temperatures below which the parasites cannot develop, i.e. 1618°C for Plasmodium falciparum and 1416°C for Plasmodium vivax. A 3°C increase in mean global temperatures is predicted to cause an increase of several million case of malaria annually. At the present time, 300 to 500 million people in the world are infected with malaria. This could increase four- to five-fold if significant (up to 3°C) global warming occurred.20 In east Africa a relatively small increase in winter temperature could result in falciparum malaria extending to higher altitudes, for example to Nairobi and Harareboth malaria-free cities at the present time. There is also the possibility of malaria being re-introduced into former malarious areas such as southern Europe, northern Australia and the USA. However, this is less likely because of effective surveillance and control programmes.
Other parasitic diseases that could extend current geographic areas of endemicity include schistosomiasis, trypanosomiasis and also filariasis.19
Arbovirus diseases such as dengue fever (see above) and yellow fever could also expand their geographical distribution. It has been forecast21 that the current predictions of a rise of 2°C in climate temperature can be expected to produce significant latitudinal and altitudinal change in the distribution of dengue.
In the UK it has been postulated that higher winter temperatures could produce a longer breeding period for rats and thus an increase in the rat population, leading to a resurgence of leptospirosis, and also to an increase in ticks causing a greater prevalence of Lyme disease.22
Low-lying countries, e.g. Bangladesh, that are already subject to frequent flooding, could suffer further as a result of higher sea levels leading to an increased prevalence of waterborne diseases such as cholera. Bacillary and amoebic dysentery could also increase as public health measures fail.
To summarize, a relatively small increase in mean world temperatures could result in certain infections, many of which today are considered to be tropical diseases, becoming prevalent in subtropical countries and even in those with temperate climates.18 The requirement for chemotherapeutic agents to treat these infections, especially those caused by resistant organisms such as falciparum malaria and virus infections, will become more urgent and also more relevant to those living outside the tropics.
Zoonoses
The relationship between humans and their animals has always been a fragile and complex one in the context of infectious diseases. Recent examples of the unpredictability and unexpected appearance of the zoonoses around the world include human immunodeficiency virus (HIV) infection, probably originating in Africa, and new variant CreutzfeldJacob disease in the UK. The latter, as well as several other important zoonotic infections not responsive to antimicrobial chemotherapy, including hantavirus infection and infections caused by the protozoal organism Cryptosporidium parvum, are not responsive to antimicrobial chemotherapy.
An example of emerging zoonotic viral infections is provided by the recently recognized paramyxoviruses. One such is the Nipah virus of pigs, which has caused fatal encephalitis in humans in Malaysia.23 The recently recognized hendra respiratory virus of racehorses in Australia has also affected humans.24
Xenotransplantation, the transplantation into humans of tissues from animals, is an exciting prospect in view of the shortage of human donor organs and tissues. Pig tissue is particularly suitable for this purpose and porcine skin, heart valves and pancreatic tissue have been transplanted into humans. Pigs' livers and kidneys have been used for perfusion of human blood of patients with hepatic and renal failure. There has, however, been concern about the possibility of infectious agents being transmitted from pigs to humans. Particular attention has been focused on porcine endogenous retroviruses (PERVs), which are permanently integrated into the genomes of pigs. Weiss and colleagues25 found that PERVs can infect human cells in culture. Although Paradis and colleagues,26 using PCR technology, have reported that they could find no evidence of PERV infection in the serum of 160 patients who had been treated with various pig tissues up to 12 years earlier, Robin Weiss,27 in an editorial in the same issue of Science, noted, It took more than 20 years for HIV-1 to spread out of Africa. The problem of maintaining vigilance over xenotransplantation should not be overestimated. We could hear more in the twenty-first century about threats to human health caused by animal retroviruses other than HIV.
Summary
Unlike many distinguished contemporaries in the 1960s, Paul Garrod did not believe that the introduction of antimicrobial chemotherapy would result in the end of the morbidity and mortality caused by infectious diseases. In this lecture I have speculated about the prospects for infectious diseases in the twenty-first century. There will be daunting challenges for antimicrobial chemotherapy. Even the one infection that has been eradicated from the world, smallpox, remains a potential threat.
Notes
* Tel: +44-121-414-6964; Fax: +44-121-414-6956; E-mail: a.m.geddes{at}bham.ac.uk
References
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