Crimean-Congo hemorrhagic fever: a disease mainly transmitted by ticks

I august 2016 fikk en uheldig turgåer utenfor Madrid et flåttbitt som skulle få fatale konsekvenser.
Flåtten var bærer av CCHF-virus. Mannen døde i løpet av kort tid, og hendelsen resulterte i at
en del mennesker (hovedsakelig helsepersonell) måtte på isolasjon i frykt for smitte:  ECDC

En av Europas mest kjente forskere på flått og flåttbårne sykdommer, professor Agustín Estrada-Peña,
fant CCHF-viruset i flått sørvest i Spania sammen med sitt team, allerede i 2010. Funnet forandret radikalt synet
på utbredelsen av det dødelige viruset. 

Professor Estrada-Peña har skrevet en svært interessant artikkel til NLBF om CCHF-virus,
og vi har også fått tillatelse til å bruke hans private illustrasjoner (slides): Crimean-Congo hemorrhagic fever: a disease mainly transmitted by ticks

Agustín Estrada-Peña, born in 1959, is Professor of Zoonoses at the University of Zaragoza (Spain). The research of Prof. Estrada-Peña is focused on the ticks and tick-borne pathogens, exploring different aspects of the identification of ticks, its distribution, and the use of satellite-derived data to understand the patterns of distribution of the ticks. The main interest of Prof. Estrada-Peña is the development of statistical tools capturing the relationships of the ticks, the vertebrates used as hosts, and the resulting patterns of circulation of different tick-borne pathogens. Prof. Estrada-Peña and his team participate in several projects supported by European funds, including i.e. the mapping of the spatial distribution of the infection rates of ticks with Borrelia in Europe. This is the etiological agent of Lyme borreliosis, and the aim is to capture the epidemiological reasons behind the contrasting rates of infection of ticks in the target territory. The team is also interested on the epidemiological patterns of Crimean-Congo hemorrhagic fever and coordinated the efforts leading to the first detection of the virus in Spain.

Crimean-Congo hemorrhagic fever is a severe viral disease mainly transmitted by the bite of ticks of the genus Hyalomma (slide 1). The virus is distributed in much of Africa, the Mediterranean basin and Asia, anywhere where several species of Hyalomma ticks exist. The ticks of the genus Hyalomma are large ticks (slide 2), very aggressive for humans, which prefer a steppe or even semi-desert vegetation (slide 3). This vegetation is an indicator that these ticks are able to support low relative humidity and high variations of temperature (warm summers and cold winters). It is important to note that our knowledge of this virus is still fragmentary, mainly because the etiological agent needs the highest containment measures available. Therefore, the capacity to perform laboratory tests is much constrained because the lack of suitable facilities to work with infected ticks or animals. The finding of the first autochthonous cases in Spain in August, 2016, changed completely our view of the distribution of the virus and outdated the known maps of the distribution of the disease (slide 4).

Every tick has three stages in its life cycle (larva, nymph, and adult) that, in the case of Hyalomma, may co-exist in the same host (slide 5). The larvae hatch from the eggs and feed commonly on small mammals, which may have the virus circulating in the blood. Therefore, larvae become infected when feeding on these viremic hosts: hares and other small mammals have been identified as hosts that can support the circulation of the virus. Most important, larvae moult while attached to the host, and resulting nymphs are infected by the virus. These nymphs feed again on the same hosts, and may infect newly incoming larvae by a mechanism called “infection by co-feeding”. This is a very important feature in the circulation of the virus, since we know that the viremia (the time the virus is circulating in the vertebrate’s blood) is very short, not more than 4-6 days. Therefore, the ability of the vertebrates to infect new ticks is very limited. In the infection by co-feeding, newly attached larvae may become infected by the saliva of infected nymphs, which feed in close proximity of the feeding larvae, without viremia in the host. This is of importance because it is not necessary that the vertebrate host develop a viremia, since one infected tick can infect other ticks by the simple fact of feeding nearby. Adults will feed commonly on large ungulates (including livestock) and again, infected adult ticks can infect naive ticks feeding in its proximity. The virus is passed by the females to the eggs.

One of the main concerns in the dissemination of the tick and the virus is that birds are common carriers of larvae and nymphs of Hyalomma (slide 6). Migratory birds follow several routes, while flying every spring from Africa to Europe. Birds “pick up” ticks at the many stops in the route, and introduce infected ticks into Europe. However, birds do not develop viremia, they just transport Hyalomma ticks, that may be infected. Concerns exist about the northern limit of distribution of the tick. Because the long lasting trend towards shorter and warmer autumns and winter, the tick is being present in central European countries, where it has been never found before. In the year 2014, we found that the tick has permanent populations in southern France, an extreme which was never confirmed before. So, the tick needs a suitable weather to survive, and the movements of either domestic or wild animals to colonise new territories (slide 7). There are reports of Hyalomma ticks found on migratory birds far north Scandinavia, but no records of permanent populations exist northern than the Mediterranean region.

Crimean-Congo hemorrhagic fever is a puzzling problem for human health. The trend towards warmer climate makes a larger suitable area for colonisation by the tick. New permanent populations have been found only in France (but there is a lack of active surveillance in other countries) and birds infected with these ticks have been collected as north as United Kingdom. Whether we are facing a new human health issue as a consequence of the climate trends is something that can be addressed only with reliable field surveys in the European countries. Modelling strategies may be of help in understanding the trends, but they calamitously fail when trying to capture local patterns. In other words, models can provide a general picture (i.e. of the complete Europe) but it is simply impossible to decide what will happen in a small territory. In the slides 8 to 12, the results of modelling the life cycle of the tick on a large set of climate data of Europe are included for the years 1901 and 2009. Our team applied several modelling techniques to obtain the mapping of “categories of suitability” for the main tick vector of CCHF in the Mediterranean, H. marginatum. The results show the spatial distribution of “extremely suita-ble habitat” marked with the category “1” to “extremely poor habitat” marked with the category “5”. The results are summarized at intervals of approximately 20 years, with a final summary in the slide 13. It is obvious that the suitable habitat is slowly spreading northern to the reported area of distribution of H. marginatum, which was restricted to the pure Mediterranean region. This trend can be observed only in the long-term, and cannot be captured if too short intervals of time are studied. Large oscillations in weather may happen from one year to another, and therefore a short time scale of observations is not enough to capture these patterns. This is why modelling strategies are useful to capture long-term patterns.

The finding of the virus in south-western Spain in the year 2010 radically changed the view of the spatial distribution of this deadly virus. The genetic sequence of the virus clearly demonstrated that it is almost identical to the strains circulating in Mauritania and Senegal. Therefore, the introduction by migratory birds carrying infected ticks was the most obvious explanation. We do not know if the virus was recently introduced in Spain, or it circulates since a long time ago. We anticipated that the virus should be present in Spain, and most probably, Portugal. This expectation was obtained by the simple examination of the distribution of the tick vector and the migratory routes of the birds. However, the finding of the virus was counter-balanced by another striking observation: why human clinical cases of CCHF were not reported in Spain or Portugal? Even for unexperienced practitioners, CCHF has a very conspicuous clinical picture, in which haemorrhages are usually prominent and easily noticed. Since the year 2010, our team has been surveying the virus in the same area of the original finding, every year giving positive results: this immediately translates into an epidemiological active focus. We do not know yet if the focus is larger than the yet small surveyed area, or if the movements of livestock carrying infected ticks can disperse the virus to relatively near areas. Current studies resulted in the collection from the field of more than 9,000 ticks, which are now in the pipeline of PCR detection of the virus at the National Centre for Microbiological Reference in Spain.

Future research should be based in understanding the epidemiological and pathogenic properties of the strains of the virus circulating in its area of distribution in the Mediterranean, as well as to ascertain the role of birds in dispersing infected ticks. The development of active surveys at critical sites of the Mediterranean region would be a critical step to ascertain if the virus is already there. An important issue is that the virus is a biosafety containment organism of category 4, the highest. These facilities are not available in every country. Even with the adequate containment facilities, the handling of infected colonies of ticks is not easy and the establishment of a laboratory model is difficult. Laboratory work should be ideally complemented by field obtained data. Field studies should be focused on the role of small mammals to support the circulation of the virus, infecting large numbers of immature ticks, and amplifying the infection in the population of the ticks.

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