It is all about infection

The notion that most diseases are caused by or associated with infections has not penetrated sufficiently into the medical community nor to society at large. This was one of the reasons why a symposium entitled ‘It is all about infection’ was held at the Karolinska Institute in Stockholm (9 and 10 June 2006). The other main reason for calling it was to demonstrate the width of the subject and the need for interaction between scientists from developing versus developed countries over common issues pertaining to infections. The penetration of infectious diseases into areas such as internal medicine and surgery is best illustrated by the demonstration of Helicobacter pylori as a causative agent of peptic ulcer, a discovery awarded with the Nobel Prize of Medicine 2005. The appropriate treatment of this infection is now antibiotics rather than surgery, which had so far been routine using the century old techniques of resection according to Billroth. Imagine how much human tissue that has been taken out, what much pain, costs and fatalities has been caused until the proper origin of this extremely common infection not the least in developing countries was revealed. Personally, I am convinced that the same will be true for ulcerative colitis and Crohn's disease, two enteric conditions for which infectious origin has been repeatedly claimed but the findings have so far not been conclusive and able to stand Koch's postulates. Thus, colectomies are still done as a final treatment of ulcerative colitis and resections of small and large bowel in severe Crohn's disease with all the debilitating side effects such invasive treatments have. I believe one reason for lack of success so far in finding their infectious origin (the same is true for multiple sclerosis) is the reductionist approach, i.e. the search for one single causative agent for each of these diseases or the assumption of a homogeneous nature of one given pathogen. I believe it to be more likely that many different agents can trigger immune reactions resulting in either ulcerative colitis/Crohn's disease if in the bowel or multiple sclerosis if in the central nervous system, all depending on the gene susceptibility of the host. In one of the four presentations from the above conference Erwin Schurr from McGill University [1] introduces a relatively new concept pertaining to this, the gene environment concept. He studies susceptibility to mycobacterial infections such as leprosy and tuberculosis (where only a minority of exposed individuals come down with disease symptoms) and he finds that under certain environment conditions (as high or low pressure of pathogens) genes related to inflammation and/or immune responses can be turned off or on resulting in various responses and penetrance/presentation of clinical disease. The reported finding comes from the study of a large extended aboriginal family in northern Canada of 81 individuals where the index case spread tuberculosis to 24 members within 6 months, a fairly ‘clean’ study situation both genetically and epidemiologically. The finding of a tight interdependence between genes and environment somehow takes the steam out of the discussion whether genes or environment are the main players in responses to infections. The somewhat lukewarm answer would be both if the results of Schurr and others [1] have some general validity. However according to Schurr [1], there will still be polar situations with disease outcome regardless of gene make up and the other way around. An intriguing question in infectious disease medicine has been why, e.g. measles has such high mortality in low-income countries in, e.g. West Africa compared with the situation in high-income countries-like Denmark even before vaccination was introduced. Was it due to genetic or nutritional (environment) differences as there was little pathogen diversity between the measles virus circulating in these different corners of the world? The Danish anthropologist Peter Aaby [2] began to study this in Guinea Bissau some 30 years ago and his controversial findings were that nutrition played little or no role (which was the dogma at the time) whereas the dose of infection appeared decisive. Measles death came more often to households with many kids and it was the secondary or tertiary cases that died and not the index case who attracted the infection in the outside (low dose) and brought it home. Index cases were commonly boys who tend to play in the outside whereas their sisters stayed more at home helping their mothers. Going through old Danish records from times when households with many children were kept in small houses he found that the mortality of measles was similar to what it can be now in West Africa (up to 50% mortality in children under 5 years during an intense epidemic in an unvaccinated environment) with the same difference between index and secondary cases and between sexes. Aaby's further studies [2] have revealed that natural measles infection as well as measles vaccine protects against death in a low-income country such as Guinea Bissau, i.e. children vaccinated against measles (live vaccine) survive better than unvaccinated children and this difference is not due to an effect on measles as such but to a so-called nontarget effect which is clearly different between boys and girls. BCG (live attenuated Mycobacterium bovis) vaccine has a similar effect (protection against death beyond the effect against tuberculosis) whereas the reverse can be true for vaccines against diphtheria, pertussis, tetanus (DPT, nonlive vaccines) which result in increased overall mortality despite protection against these three infectious diseases. Aaby [2] withholds that the nontarget effect of vaccines may be as or sometimes even more important than the targeted effect and it has to be taken into account in designing vaccine programmes. His data and conclusions are still controversial and mainly based on descriptive studies but if true they point to important roles of pathogens in affecting immune responsiveness in general which is linked to survival and under sex/gender influence. The field of infectious diseases has been totally dominated by the HIV epidemic the last decades with SARS and Avian flue as some late but prudent contenders. Our profession was taken by total surprise although we ought to have known that any population that increase in number such as man and has such unprecedented mobility is bound to be hit by ‘new’ epidemics. Mostly the information about the HIV epidemic has been apocalyptic so far and it is not until the introduction of a multidrug therapy, which has the ability to halt the infection that some light has been seen also for the victims. Although the structure and biology of this very complicated virus was revealed in a very short time, the making of a protective vaccine has failed totally so far despite numerous attempts and billions of dollars. This in contrast to situation with another even more complex virus – smallpox – where an efficient vaccine was made without even knowing what a virus or a microorganism was and for a cost of probably <1000 USD (Jenner 1798). Why is this? The answer is nobody knows but one explanation may be that natural infection with HIV results in an immunity which is not protective at all in the long run in contrast to a small pox infection which results in lifelong protective immunity if you survive. Thus, vaccine scientists have no ‘natural’ immunity that they can try to replicate when it comes to HIV. They must try to make something that nature has not managed so far. And the so far may be important. Chimpanzees harbour an almost identical virus, SIV-1 that shows very little pathogenicity. These primates have been around for much longer than man and thus probably they have lived (and died) with the virus for thousand of years whereas man may not have been in epidemic contact with HIV-1 for more than a century at the most. The latter is not enough to select for immune response genes that can neutralize the infection. However, Jean-Marie Andrieu and Wei and from Paris reported in this issue [3] for the first time that it is possible to educate human immunocompetent cells in vitro towards a virus neutralizing effect. The method he uses is both tedious and expensive but the breakthrough is that it is possible to deviate the response of the host from inability to ability to halt the infection. This autologous cell vaccine is not and will never be preventive but may be used as an adjunct or alternative to chemotherapy notably in situations where there is multidrug resistance. However, the immunity it raises can be one that a conventional microbial vaccine should be looking for. An even more positive note [4] comes from a group under Dr Dawit Wolday et al. from the Ethiopian Nutrition and Health Research Instititute (ENHRI) in Addis Ababa, Ethiopia. They have analysed sera for HIV antibodies from mothers attending antenatal care in Addis Ababa between 1995 and 2003, altogether 7700 sera. During this period the prevalence has fallen from 7% to 2%. But in addition the incidence (new cases per year determined by a method that uses titre of antibody as indicator of duration of infection) has dropped even more steeply especially in the youngest age groups. The finding in this study corroborates with an increasing number of others from the same region of Africa (east-central), i.e. the one where the epidemic once started and repeatedly the decline is most strongly noted in the young urban population, which is the one that was most rapidly hit at the onset of the epidemic. This declining trend has been observed for many years but it is not until in the latest UNAIDS report (2005) that it is commented upon although as a minor thing compared with the upsurge of the epidemic in the former Sovjet states. However, research into why the epidemic is coming down where it once started is of utmost potential importance because the only thing we know is that it cannot be for the same reason as for most other epidemics, i.e. development of herd immunity as there is none of that for HIV. For a virus with such low infectivity (maybe 20 times less infectious than hepatitis B virus through the same route) it may suffice with minor behavioural changes to reach considerable preventive effects. Efforts in searching for a social vaccine is highly warranted but has low prestige and support in the scientific community today. No conflict of interest was declared.

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