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Epidemiology of imported infections

Dr. Helmut Jäger, MD Medicus

Temos Conference 20.-22-11.2011, Session "Germs, viruses & Co: unrequested passengers“ in medical tourism", Tuesday 22. Nov. 2011

We are facing a paradigm shift in infectiology.

One of the deadliest pandemics in history was the Black Death in the 14th century. It almost whipped out half of the population in Europe. This gave rise to the hypotheses, that some Ebola-like infection and not Yersina pestis (Y.p.) was the true cause of the Black Death epidemic.

A study recently published in Nature could prove, that it was indeed Y.p.. Human remains from a London cemetery of pest victims were examined and it was possible to reconstruct nearly the whole genome of Y.p. Comparisons with the modern genome of Y.p. revealed no unique derived positions in the ancient organism, indicating that the perceived increased virulence of the disease during the Black Death may not have been due to bacterial phenotype. These findings support the notion that also factors other than microbial genetics, such as environment, vector dynamics and host susceptibility, should be at the forefront of epidemiological discussions. To stress this point further I like to take Cholera as an example. Cholera has been scrutinized by epidemiologists since the birth of epidemiology. Currently we are facing the 7th Cholera-Pandemic, a devastating one.
And Cholera is still very useful to learn our lessons concerning infections and inflammation. This mural was painted in West Africa where more than 90.000 cases were registered from January till October this year.

After a devastating earthquake, rendering three Million people homeless, the pandemic reached Haiti. On the basis of genetic analysis it is almost certain that the Vibrio’s were introduced to Haiti by UN Peacekeeping forces from Nepal.

But none of the soldiers was suffering from cholera when they arrived in Haiti. Why could this happen? And why is the epidemic again very active so that we expect 500.000 cases since the earthquake by the end of this year. In order to find an answer I like to digress here for a moment and have a look, what we learned from previous cholera epidemics. Cholera transmission depends on unsafe drinking water supply, and still the supply in Haiti is still far from being secure. 150 years ago Rudolf Virchow showed in different studies that epidemics arise as a consequence of various social factors. And ill health often results from living in subhuman conditions and from lack of education.  Therefore, Cholera can be regarded as an indicator of intolerable social conditions. And as long as these conditions prevail health care alone will not improve the situation dramatically.  The great cholera epidemic in Hamburg 1892 was the breakthrough of a new idea. Koch and Pasteur laid the foundation of the germ theory:

Humans have to defend themselves against enemies. And enemies can be identified, isolated and destroyed. The war metaphors of this theory reflected the main stream thinking in this period of time. Finally with the discovery of penicillin the Germ Theory dominated the debate on infectious diseases. Nevertheless in the case of cholera antibiotics are rather useless, as the only effective treatment of cholera includes re-hydration and the restitution of electrolytes. Nevertheless, cholera is treated with antibiotics worldwide, also given some times for prophylactic purposes, thus favoring antibiotic resistant strains.  Florence Nightingale stressed the importance of care, rather than treatment. She found out that the chances for survival increased dramatically if the patients received a certain quality of care and enough clean drinking water. In Bangladesh morbidity and mortality of cholera depended on pre-existing health and nutrition status, duration of dehydration and last but not least on the quality of care, avoiding hospital infections like pneumonia.

Another theory is almost forgotten: Max von Pettenkofer, like Virchow an effective organizer of healthy urban living conditions, developed a rather complex theory of an otherwise harmless microorganism which would transform itself in the presence of excrements and dirt in the soil into something dangerous. He was wrong about an airborne origin of cholera, but he was right in assuming that causative agents of cholera vary over time in an endemic setting due to ecological factors. Vibrio’s are part of the plankton community of coastal ecosystems. They live in particular in a crustacean (copepod). The development of Vibrio’s from dormant, not infectious states to an infectious phase is triggered by increasing water temperature and a variety of other factors (seawater nutrients, commensal algae, pH, decrease of salinity). Heavy rainfall and overflow of pit latrines increases the risk and may start an epidemic. If these factors are monitored, which has been the case in a recent study in Zanzibar, the fluctuation of epidemics could be predicted. Another lost, nevertheless important hypothesis targets the internal causes of disease. Antoine Béchamp was an important microbiologist in the 19th century. It was he, who identified “little bodies” 15 years in advance of his colleague and later opponent Pasteur. He described infections as a result of efforts of the host organism to control them. Therefore he proposed that infection was a consequence of bad health. And indeed also Béchamp proved to be on the right track. Explosive outbreaks are caused by biofilm-induced infectivity. The formation of biofilm-derived Vibrio’s necessitates a passage through the human intestine. These hyper-infective forms are quite different from those of planktonic cells and very short lived. They decay in lower infectiousness states within hours. Therefore the Human-to-human Transmission is crucial.

Cholera now lingers in many coastal ecosystems, and if governments don’t learn their lessons from previous epidemics their populations will continue to live with time bombs. Ecuador is an example. It experienced a cholera epidemic 1991. The red line indicates the cholera cases which came to zero. Nevertheless cases of severe diarrhea went up steadily, indicating that water supply and living conditions have not improved since. Therefore it seems to be only a question of time when the next outbreak in Quito will occur.

But Ecuador is far away. Why should we care?

All tropical diseases are rare events in Germany, accounting for only 1-2 cases per 100.000 populations (RKI). Yes, infectious diseases are worldwide on the rise but they are spreading mostly in warm climate zones and social disadvantaged population groups. Nevertheless, also the rich northern hemisphere is confronted with the ever larger number of emerging diseases, sources being wildlife, domestic animals, vector born infections and drug resistant bacteria. The epidemiology of SARS is a good example of s.th nasty that luckily could be controlled by public health efforts. Epidemiology in recent years has made important progress and in some regions we are able to monitor epidemics by the spread from one household to another, like in this example of chikungunya-infections per households in Réunion. The flip-side of the coin of modern epidemiology is an ever-growing epidemic of epidemics in the media. Scare stories and virtual epidemics may cause panic, and thereby may be damaging to rational health policies. And worst case scenarios may replace reasoning by evidence.

A real threat arises with high and often irrational antibiotic use resulting in resistance. The development of resistance follows a rule of classical selection, the survival of the fittest. The most recent example is NDM-1, a bit of information shared between microorganisms. This plasmid renders the bacteria which integrate it in their metabolic system resistant against all known antibiotic groups. Associated Factors in India were hygiene and high and uncontrolled use of antibiotics. It was rapidly transmitted from India to Europe and North America by patients traveling to India for elective surgery. Meanwhile it is present in the drinking water supply in New Delhi. And recently it caused an outbreak in Johannesburg. Needles are another source of infections in many countries. Hepatitis C is a very good marker of nosocomial infections, and if a law institution in the US advertises legal support in supermarkets it must be frequent.  WHO describes its even greater importance in many other parts of the world.
In some African and Asian countries up to 25% of HIV transmissions were acquired in the health care system by reused needles, unsterilized materials and blood transfusion. 

20 years ago I conducted a study in urban Kinshasa (Projet SIDA). 28% of blood bags ready for transfusion had bacterial contamination. Health care in this setting was very dangerous to health, and the situation since has not changed very much in many parts of the world.
Here some recent examples from India, a major target of medical tourism:

There is a additional lesson we can learn from form the recent EHEC (E coli O157:H4, Shiga toxin + Enhanced adherence) epidemic in Germany from May to July 2011: The importance of the immune reaction to external disturbance. The EHEC epidemic indicates the risks associated with the globalization of food production. The Microorganism was not new but the population naïve to it. We don’t know how many persons came in contact with this microorganism. The Ratio EHEC-Contact / Symptoms are unknown. More than 3.000 cases were notified and 50 of them died. More than 800 developed Hemolytic uremic syndrome (HUS, 30% of them with severe neurological symptoms. Antibiotics were useless and even dangerous: because suppression of competing microbiota and decomposition of bacteria caused a higher concentration of Shigatoxin. Indeed useful was Public Health, identification of cases and contacts and surveillance. Two therapeutic approaches seemed to be effective: Modulating Immune response with Eculizumap (C5 / C5a, suppression of the complement cascade) and Immunoabsorption (IgG depletion).

Disease is not the aim of a microorganism, it`s destiny is to reproduce. Virulence often results from “screw-ups” by the host’s immune system. Therefore we should concentrate more on the interaction between microorganisms, the ecological systems in which they evolve and the factors of host response.

The late Joshua Lederberg, Nobel Laureate and leading expert on emerging diseases in the USA, reminds us that the interactions between living organisms are complex: He suggested we should revise our behavior in order to avoid the emergence of new germs through the environment or health care associated sources. And we should use the war metaphor in infectiology only in cases of life threatening emergencies and otherwise replace it with an ecological one:

Inflammation can be regarded as a complex form of communication. Understanding inflammatory and anti-inflammatory reflexes may lead to better treatment outcomes and to the development of new drugs or even devices to reprogram inflammation instead of suppressing it.

 

HEF, MG, 15.11.2012