Abstract
Dr. Gail Thomson is Consultant in Infectious Diseases at Royal Liverpool University Hospital & Department of Medical Affairs, Health Protection Agency, Porton, United Kingdom. She received her Bachelor of Medicine degree and MRCP certification from the University of Edinburgh, Scotland, and her Diploma of Tropical Medicine & Hygiene from the University of Liverpool. Dr. Thomson completed post-graduate training in Infectious Diseases and spent a year and a half at WHO Geneva working as part of the SARS team, Turkey H5 event and outbreak response and training of health care workers. Her areas of research and clinical interest include viral hemorrhagic fevers, outbreak response, emerging pathogen research and response, clinical networks, and healthcare worker safety with regard to infectious diseases.
In 2000, I had the opportunity to assist in the international response to support Uganda in its efforts to control the outbreak of Ebola. I was given this opportunity to help by the World Health Organization (WHO) and by my hospital at the time, North Manchester General Hospital. I found my experience in Gulu a very humbling experience. Despite the challenges of the outbreak, I did enjoy working alongside amazing local staff and colleagues from Japan, the U.S. Centers for Disease Control and Prevention (CDC), and Doctors without Borders/Médecins Sans Frontières (MSF). Subsequently, I received other invitations to join the WHO Global Outbreak Alert and Response Network (GOARN) responses to Ebola, Marburg, and Crimean-Congo hemorrhagic fever (CCHF) outbreaks in various countries. Through these short missions I have developed an interest in healthcare worker (HCW) safety and training. I also realized that it takes a multidisciplinary response to prevent and control CCHF, and that the coordination and integration of those teams is crucial.
I am not certain one can say “recent,” as time is required for all the factors that contribute to the transmission cycle to come together to allow for the disease to flourish and have an impact on humans. Let me expand on some of those core factors.
Currently, foci of CCHF virus (CCHFv) are emerging in parts of Eastern Europe and Central Asia with no obvious pattern to the driving forces behind the transmission given that the tick and wildlife fauna in neighbouring epidemic and non-epidemic zones exhibit no obvious difference. Therefore, the study of enzootic cycles is a priority research area. By understanding how the disease cycle works one can try to break that cycle. The possibility of unravelling the enigmatic nature of the enzootic cycle is achievable through an integrated approach that considers the impact of multiple factors: • Human behavior and practice in relation to the disease; • Exposure to ticks; • Land management and animal husbandry.
CCHF is predominantly a tick-borne disease, although cases can also occur through contact with infected blood from both humans and animals. Therefore, one area of focus has to be on the tick. However, the distribution of the known tick vector species Hyalomma far exceeds that of the virus. It is generally considered that in areas where H. marginatum occurs and hares and ground feeding birds frequent, there is the potential risk of CCHFv circulation. Hyalomma ticks have a greater capacity than any other tick species to adapt to new environmental conditions and are known to be transported across continents on migratory birds. This is one area that needs further study to determine the conditions that allow for them to become established and their subsequent involvement in disease transmission.
Another noteworthy point is that temperature impacts positively on Hyalomma ticks, with development rates and activity correlating with temperature. Circulation of CCHFv in ticks and consequent CCHF outbreaks have been linked to large increases in the density of the Hyalomma population as a result of a fortuitous combination of optimum weather during the critical winter-spring season and environmental changes caused by war or by new agricultural practices.
I would identify four main challenges: classification, shipment, confirmation of diagnosis, and funding. Classification of CCHFv as a pathogen necessitates the highest level of biocontainment. CCHFv is characterized as “Risk Group 4” (high individual and community risk): a pathogen that usually causes serious human or animal disease and that can be readily transmitted from one individual to another, directly or indirectly.
Biosafety Level 4 can be a hindrance to the study of the virus, and some of the endemic countries do not have the capability to study it. This is where collaboration with those that do and capacity building is essential. However, there are challenges related to the shipment of samples across borders, and this may make collaboration more difficult. These challenges may include logistical issues to ensure that samples are stored and moved fast enough to allow for antigen detection.
In countries that do not have access to rapid and robust laboratory confirmation capabilities, diagnostic confirmation may be delayed, necessitating reliance on a clinical diagnosis. The differential diagnosis of CCHF includes Hanta virus infection and leptospirosis. The decision to include CCHF in the differential diagnosis has an impact on the infection control measures to be applied. In turn, other investigations may be delayed as there will be concern over the potential for nosocomial amplification of infection in the health care setting.
All of these complicating factors require funding. With sufficient support for training, assay transfer, biosafety guidance, and multidisciplinary activities, the generic skills developed for working with CCHFv can be taken and applied to other dangerous and emerging pathogens.
The main problems can be described using the acronym ABCDE: • • • • •
Overall, vigilance and safety precautions are essential for all patient-related activities, such as venipuncture and laboratory analysis of samples.
Supportive care is given to all suspected or confirmed CCHF cases in the hospital. This includes fluid management and blood products. There is a need to develop standardized supportive care protocols that can be validated and shared. We in the field of CCHF are very interested in working with our colleagues in the world of dengue who have made excellent progress in this area.
A drug called ribavirin is used widely in the treatment of CCHF. However, the quality of the evidence base is limited due to the difficulties in studying this disease and the reality is that clinicians will be keen to give a drug if there is any chance it will help. To help determine the efficacy of ribavirin once and for all, a multi-center randomized, controlled trial might be considered as an international collaborative effort.
CCHFv is spread via direct blood contact from other infected humans or viremic animals or by tick bite. The estimated ratio of disease to subclinical infection suggests a higher risk than other arboviral infections.
Interestingly, the length of the incubation period for the illness appears to depend on the mode of acquisition of the virus and the virus dose. Following infection via tick bite, the incubation period is usually one to three days, with a maximum of nine days. The incubation period following contact with infected blood or tissues is usually five to six days, with a documented maximum of 13 days.
Generally speaking, patients are symptomatic enough to require hospitalization. The patient is likely to develop an abrupt high fever with other non-specific symptoms. There may be a history of occupational exposure or a recent tick bite. The tick may still be in situ and, therefore, the patient should be thoroughly examined and any ticks carefully removed.
CCHF may be relatively mild, but it may also cause the most dramatic ecchymoses, nose bleeds, and gastrointestinal bleeding of all the viral hemorrhagic fevers, which puts HCWs at risk if the appropriate precautions are not in place. Atypical presentations combined with a lack of awareness may, for example, result in a patient undergoing abdominal surgery. The Case Fatality Rate, as reported by WHO, may be as high as 30%, but it is often much lower.
For the prevention and control of CCHF there must be an integrated multidisciplinary approach to provide an understanding of all elements of the transmission cycle. If we are to understand the spatial and temporal occurrence of human disease we must understand the ecology of the virus in nature. Medical ecologists and medical entomologists have extensive experience in disease ecology which has been and is being applied to other vector-borne pathogens. Considering the nature of CCHF virus, inclusion of these disciplines is integral to identifying novel interventions for disease outbreaks and preparing for them.
A better understanding of how CCHF is transmitted and what behaviors influence its transmission, which may vary from country to country, will help to ensure that the public health messages are right for at-risk populations. We also need to consider appropriate dissemination and follow-up.
Ecology and entomology: The study of enzootic cycles is a priority research area. By understanding how the disease cycle works one can try to break that cycle. The possibility of unravelling the enigmatic nature of the enzootic cycle is achievable through an integrated approach that considers the impact of the three main factors I mentioned previously–human behavior and practice in relation to the disease; exposure to ticks; and land management and animal husbandry.
How ticks adapt to their environment and how they adapt to a new environment when, for example, they are transported via migratory birds, is one area that needs further study to determine the conditions that allow the ticks to become established and foster their subsequent involvement in disease transmission. Another important area is the development of mapping and modelling strategies for predicting risk and helping to understand the abiotic niche of CCHFv and the changing trends and potential for expansion, across Europe, for example.
Virology and diagnostics: Some basic questions remain unanswered even regarding the basic virology. Other considerations include pathogenicity determinants and the need for rapid, robust diagnostics.
Vaccine development: This has been hindered by the lack of a suitable animal model; however, there are currently groups across the world working on a CCHF vaccine. We have an effort underway here at Porton.
Epidemiology and public health messages: Surveillance to provide a better understanding of the global spread of disease and awareness of at-risk groups. I would also include in this category, the behavior of HCWs and of the public, which requires further study.
Clinical: A randomized, controlled clinical trial to assess the efficacy of ribavirin in CCHF; supportive care protocols; development of new drugs; an understanding of what happens at a cellular level in a severe case of disease.
It is crucial to encourage a global spirit of collaboration, capacity building, lessons learned, and sharing of data, study protocols, and samples to help speed up the answers to a variety of questions. This spirit is being encouraged by some of the big funders in the area of respiratory infection. Plus, there are various consortia around the world that have already taken on this attitude towards research.
We have set up a multi-disciplinary, international consortium called the Integrated Global Action on Crimean Congo Haemorrhagic Fever (IGAACC), and we have a web site that is in its infancy,
By having an integrated approach across the disciplines we can try to intervene at the most appropriate stages to have the biggest impact. Also, by working closely with other disciplines, the understanding of all aspects of the disease will improve, which will help with the research effort, including when an actual response to an outbreak is required. One aim could be to integrate clinical research into routine practice; to set up core capabilities that could be utilized when an outbreak happens. Integrated data collection tools could also service case management, surveillance, and research needs. Generic lessons are being learned and preparations can be made for other emerging pathogens based on the work done on CCHF.