C. Nederstigt (1,2), W.M.J. Pelt (1), J. van Paassen (1), D.J. van Westerloo (1)
1 Department of Intensive Care, Leiden University Medical Centre, Leiden, the Netherlands 2 Department of Intensive Care, Tergooi Hospital, Hilversum, the Netherlands
D.J. van Westerloo - firstname.lastname@example.org
Potential pandemic pathogens series: Crimean-Congo haemorrhagic fever
In the last two years we have experienced the effects of the COVID-19 pandemic in our lives and hospitals. Pandemics are part of the history of humanity and we can be certain that in the future new pandemics will appear. In fact, due to the growth in the human population, increased travel and global warming, it is to be expected that new pandemic pathogens will arise more frequently than before. Additionally, decreased barriers between animals and humans will give rise to spillover events, which will result in the introduction of new zoonotic pathogens in humans. In each of the parts of this series we will, in a short format, highlight a potential pandemic pathogen and describe its characteristics, history and
potential for global pandemics. This part of the series focusses on the Crimean-Congo haemorrhagic fever virus. Crimean-Congo haemorrhagic fever is a tick-borne disease, which is generally found in workers at farms and slaughterhouses and sometimes causes small outbreaks in families or hospital personal, as it can be spread by body fluids. Symptoms are unspecific, including myalgia, headache and fever. The disease course is often mild, but in patients who develop a haemorrhagic phase, the fatality rate is high. Treatment is primarily supportive but antiviral therapy including favipiravir and ribavirin are under investigation.
Introduction of Crimean-Congo haemorrhagic fever
The first documented outbreaks of Crimean-Congo haemorrhagic fever (CCHF) were in the Crimean region of the former Soviet Union in 1944 and in the Belgian Congo (now the Democratic Republic of the Congo) in 1956, resulting in the current naming. The CCHF virus (CCHFV) is a member of the genus Orthonairovirus (Order: Bunyavirales, which include Hanta, Lassa and Rift valley virus) and is transmitted by a vector including various tick species, mainly Hyalomma ticks, carried by wild animals as well as domestic animals and humans. The endemic area of the CCHFV vector is gradually expanding and in the past years autochthonous infected patients are increasingly being reported in Western Europe. As CCHF is a serious disease with a high case fatality rate, better understanding of the vector, virus and patient-related factors is essential.
CCHF occurs most frequently following a tick bite, but can also be transmitted by unprotected contact with infectious blood and body fluids (figure 1). In endemic areas infection with CCHFV is common in workers at farms and slaughterhouses and in healthcare workers that come in contact with patients and their body fluids.[3,4] The usual incubation period is typically two to three days but this can last as long as nine days, and is usually shorter after a tick bite than after contact with infected blood or tissues.[2,3] Hospital admissions of CCHFV patients follow a seasonal pattern and correlate with climate parameters, with a peak of infections during the summer months,[5,6] possibly related to the conditions being favourable for ticks. Patients are predominantly male adults, mainly working in the aforementioned professions.[7-9] Although most infections with CCHFV are mild with unspecific symptoms, a high case fatality rate of hospitalised patients has been reported of up to 80% (mean 11%), resulting from multi-organ failure, shock and haemorrhage. As CCHFV infection can have a severe course and is contagious (by body fluids) to healthcare workers, it is considered a bio safety level 4 disease and it is mandatory to report to designated public authorities (Meldingsplichtige ziekte groep A). Guidelines advise to admit patients with a strong suspicion of infective haemorrhagic fever including Lassa, Ebola, Marburg and Crimean-Congo virus in strict isolation until contagious viral haemorrhagic viruses are ruled out.
The first presentation of the disease can vary with myalgia, headache, fever and photophobia followed by nausea, diarrhoea, abdominal pain and liver enlargement, eventually leading to a haemorrhagic phase with severe bleeding complications in the skin, gastrointestinal tract and ear, nose and throat area. The latter phase starts at day four and lasts for up to two weeks. This clinical picture resembles the haemorrhagic fever seen in Dengue and Ebola virus infection, although the appearance of typical large ecchymosis is quite specific for CCHF. Predictors for mortality are haemorrhage (melaena and disturbed coagulation parameters), diarrhoea and confusion.[11,12]
Since most infections are probably self-limiting with mild symptoms, it is unknown what percentage of infected patients present to healthcare facilities or are admitted to critical care units. Some studies describe co-infection of family members or co-workers with few symptoms not in need of in-hospital care, confirming a substantial proportion of subclinical and mild infections, without diagnostic confirmation in daily practice. One study estimated that 88% of infections were subclinical after seropositivity surveillance in an outbreak area. In severe cases, clinical deterioration usually occurs in a short time window with a mean time between onset of symptoms and death of around seven days.[9,14] This shows that early establishment of the diagnosis and initiation of supportive care is warranted to lower current case fatality rates.
Diagnosis, prevention and treatment
CCHFV displays a high variation in sequence diversity resulting in diagnostic challenges in establishing the diagnosis.[2,15] The use of real-time polymerase chain reaction (RT-PCR) is recommended, as it is suitable and sensitive in the early course of active infection, but is dependent on conserved genomic sequences. As immunological assays are less impacted by small genomic variation, the highest sensitivity can be achieved by combining both methods, if available.[16-18] In the Netherlands diagnostics are only available at the WHO Reference and Research Centre for Arboviruses and Haemorrhagic Fever Viruses Erasmus MC, Department of Virology, Rotterdam. Other laboratory tests are non-specific for CCHFV although, as with other viral haemorrhagic fevers, patients often present with thrombocytopenia, anaemia and elevated liver enzymes.
Currently, no specific antiviral agent against CCHFV is available and the main treatment is supportive care, even in severe cases. This includes fluid replacement, erythrocyte transfusion and supplementation of coagulation and electrolyte deficits. In severe cases additional support includes respiratory support following cerebral and pulmonary alveolar haemorrhages and also haemodialysis can be required. There is no evidence for the use of steroids or intravenous immunoglobulins in the management of CCHF, although some case studies report a positive response to plasmapheresis and/or ribavirin.[22-24] In a cohort study from 2009, there was no difference in case fatality rate between treated and untreated patients with ribavirin. Still, if initiated early in the disease course, other studies found a difference in survival rates and it has been shown to be very effective as post-exposition prophylaxis, with infection rates of 89% in untreated versus 7% in treated patients. This may indicate a time-dependent effectivity, but data are scarce and since a Cochrane meta-analysis from 2018 showed that current evidence is low, the effectivity of ribavirin is still unconfirmed. Recent evidence shows that another antiviral agent, favipiravir, may be promising as an effective treatment, possibly in combination with ribavirin, but this is still under investigation. At this moment, there is also no widely approved vaccine available to prevent CCHFV infection, although research is ongoing on this topic, targeting various subunits of the virus.
Outbreak threat potential
Up till now, outbreaks of CCHF have been reported in Russia, Africa, Eastern Europe and the Middle-East, ranging from small clusters with a few cases up to over 4000 cases, with case fatality rates varying from 0 to 80%, with a mean of 11% including over 10,000 cases. As with many pandemic pathogens, the case fatality rate of the disease is much higher in Africa than Europe (32% vs 13%), possibly as a consequence of low resources and long distances to healthcare facilities.
In Europe, CCHF is endemic throughout the Balkan states and increasingly emerging in Turkey among farmers. In some regions antibody positivity of 10% can be found in humans and even higher in livestock. In 2016 the first autochthonous case was reported in Spain, and is thought to be the effect of change in the geographic distribution of the main vector, Hyalomma ticks (figure 2). In 2016 it was also reported that the Hyalomma marginatum tick is spreading into Europe and has been found in southern Germany and the Netherlands since 2007 and 2006, respectively.[33,34]
This expansion is associated with migration of hosts, such as wild animals, mostly birds,[35-37] and livestock and has several potential risks. First, introduction of infected ticks into new areas can cause human-to-human transmissions and, second, uninfected ticks that inhabit new areas can be a potentially suitable host once CCHFV is introduced and aid persistent circulation of the virus. Changes in temperature as a consequence of climate change potentially enables introduction of ticks in currently Hyalomma-free areas. An example of rapid invasion of CCHFV is seen in Turkey; the first case emerged in 2002, after which over 1000 infections a year were seen.[32,41] Migration of livestock is one of the main concerns in the spread of Hyalomma ticks as infection in domestic animals is usually not apparent. Therefore, surveillance in animals and limitation of transport of livestock from endemic into naïve areas, acaricide treatment of exported livestock and quarantine periods are part of the current measurements to prevent spread.
CCHFV infection in travellers is rare, only 21 cases were reported from 1960 until 2016, but the case fatality rate in this group was around 60%, which is amongst the highest reported. Furthermore, two of these cases resulted in secondary (nosocomial) infections of healthcare workers due to the fact that CCHFV infection was initially not considered. Awareness of the possibility of CCHFV infection is low in non-endemic countries and may contribute to local clusters of outbreaks, as seen in other areas.[32,39,43]
Factors that contribute to better survival have not been elucidated, but various reasons have been proposed: 1) Local experience and recognition of CCHFV infection, as the case fatality rate tends to be lower in endemic areas and some authors suggest this may be a consequence of early recognition and initiation of supportive treatment, 2) Accessibility and quality of care, because the case fatality rate is among the highest in low-income countries[2,32] and 3) Genetic diversity and mutational capacity in CCHFV strains is high and novel or specific phenotypes can have reduced or increased virulence for humans and altered capacity for transmission among ticks. To date, studies that showed a higher mortality related to specific strains are rare but close monitoring is warranted.[2,44]
CCHFV is a significant threat to public health, with the potential for virus expansion into new regions and cases occurring over a wide geographic range. In some of the patients, CCHF has a serious course and currently there is no vaccine or specific treatment available. In case of large outbreaks, the high case fatality rate will probably put a heavy strain on healthcare facilities.
All authors declare no conflict of interest. No funding or financial support was received.
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