Emergence of viral hemorrhagic fevers: Is recent outbreak of crimean congo hemorrhagic fever in India an indication?C Lahariya1, MK Goel2, A Kumar2, M Puri3, A Sodhi4
1 Public Health Specialist, New Delhi, India
2 Department of Community Medicine, Post Graduate Institute of Medical Sciences, Rohtak, India
3 Department of Community Medicine, Lady Hardinge Medical College, New Delhi, India
4 Department of Community Medicine, Vardhman Mahavir Medical College and Safadarjung Hospital, New Delhi, India
The emerging and re-emerging diseases are posing a great health risk for the last few years. One such category of diseases is viral haemorrhagic fevers (VHFs), which have emerged in the new territories, worldwide. Crimean Congo Hemorrhagic Fever (CCHF) cases, for the first time in India, were reported from Gujarat, in January 2011. The emergence of diseases not reported earlier, pose great economic and social challenge, burden health system, and create panic reaction. Nonetheless, with recent experience in control of epidemic diseases, and advances in basic scientific knowledge; the public health community is better prepared for these unexpected events. This review provides information to physicians on CCHF for managing outbreak, and identifies public health measures to prevent emergence and re-emergence of VHFs (including CCHF) in future. The authors suggest that though, there are a few challenging and unanswered questions, the public health preparedness still remains the key to control emerging and re-emerging diseases. The countries where virus activities have been reported need to be prepared accordingly.
Keywords: Crimean congo hemorrhagic fever, emerging diseases, epidemics, India, viral hemorrhagic fever
Infectious diseases remain one of the biggest contributors to morbidity and mortality in the world. Some of these e.g. tuberculosis, malaria, lower respiratory tract infections, gastrointestinal diseases, and HIV/AIDS contribute to majority of disease burden.  However, a few diseases are of interest as they pose risk of epidemics in both general population and health care community. The viral hemorrhagic fevers (VHFs), i.e., Lassa, Marburg, Ebola, South American VHF, Hantaan, and Crimean-Congo, etc [Table 1] have recently emerged in the those parts of the world, where these were not reported previously, and pose a potential for significant clinical and public health hazard and epidemics. ,
A few reports of cases of Crimean Congo Haemorrhagic Fever (CCHF) from Gujarat were reported in January 2011.  This was the first time when CCHF has been reported from India. There has been limited knowledge amongst health professionals about this disease, which poses a further challenge in public health control measures. Therefore, this review was done to provide information to physicians on CCHF, as an example for managing outbreaks of VHFs. The review also aims to identify the public health measures to prevent the emergence and re-emergence of VHFs in the world.
The extensive systematic review of literature about VHF and CCHF was conducted on PubMed, Medline, EMBASE, Google Scholar, and other databases to access relevant and the latest information regarding history, situations update, and recommendations for viral hemorrhagic fevers including CCHF. The websites of the World Health Organization, news agencies, ministries of health of affected countries (including India), and various research institutes (e.g., National Institute of Virology in Pune, India etc.) were searched.
The information collected was collated and summarized. A decision was made by the authors on the most appropriate information needed for physicians and public health managers in consultation with a group of experts. Thereafter, the first draft was prepared and internally circulated for review by three independent subject experts and the input of 2 more persons. The manuscript was further revised, based upon their comments, and submitted to the journal. The further revision was done, incorporating the comments received from four independent referees.
This disease was first described in Crimea region of former USSR in 1944 and given the name Crimean hemorrhagic fever. ,,, Subsequently in 1969, it was recognized that the pathogen causing Crimean hemorrhagic fever was the same as that responsible for an illness identified in 1956 in the Congo, and linkage of the two places names resulted in the current name for the disease and the virus. ,,
CCHF is endemic in many regions of Africa, the Balkans, the Middle East, Europe and Asia, South of the 50° parallel north which corresponds with the limit of distribution of the Hyalomma tick. , Over the last several years, sporadic human cases and limited outbreaks have been increasingly reported. Outbreaks of CCHF have been recorded in a number of countries in the last decade and have drawn the attention of international community.  The disease has been reported from South Africa, Congo, Mauritania, Burkina Faso, Tanzania, Senegal (all in Africa)  Moldova, Ukrain, and many other parts of Europe. Tajikistan, Uzbekistan, Turkmenistan, Kyrgyzstan, Kazakhastan, Turkey, Bulgaria, Greece, Albania, Kosovo; and in the Middle East including in Afghanistan, Iran, Iraq, Kuwait, Oman, Saudi Arabia, Pakistan.  The last outbreak reported to World Health Organization (WHO) was from Pakistan in October 2010. , The trend seems to suggest increased disease incidence amongst humans, which partially might be attributed to the increased awareness and diagnostic capacity. However, the increasing geographical spread itself is cause of concern. CCHF is a notifiable disease to the World Organization for Animal Health (OIE) and the WHO, and notification is not related to the consequences of its spread within the animal population, but rather to the risk posed by zoonotic potential. 
The causative agent of CCHF is a Nairovirus, a group of related viruses forming one of the five genera in the Bunyaviridae family of viruses. The virus is enveloped and possesses a tripartite, negative sense, single-stranded ribo nucleic acid genome. , All of the 32 members of the Nairovirus genus are transmitted by Argasid or Ixodid ticks, but only 3 have been implicated as causes of human disease: Dugbe, Nairobi sheep viruses, and CCHF, which is the most important human pathogen amongst them. 
Reservoirs and vectors
This disease spread via Ixodid (hard) ticks from the genus Hyalomma. Boophilus, Dermacentor and Ixodes may also transmit the virus locally. Rarely, CCHF was reported from a biting midge (Culicoides spp.). It had also been found in two species of Argasidae (soft ticks); however, experimental infections suggest that CCHFV does not replicate in this family of ticks. 
CCHF virus may infect a wide range of domestic and wild animals such as deer, cattle, goats, and sheep etc. , These animals bring ticks into close contact with humans and allow transmission of the disease. Animals and birds may become infected with CCHF from the bite of infected ticks. Once infected, the tick remains infected through its developmental stages, and mature tick may transmit infection to large vertebrates including livestock. , Trans-ovarial and venereal transmission has also been demonstrated amongst some vector species, indicating a mechanism which may contribute to maintaining the circulation of the virus in the nature. 
There are two main routes of the transmission of the disease: First is the tick bite (Hyalomma marginatum and second is human to human by blood transmission.  Humans become infected with CCHF virus through direct contact with blood or other tissues from infected livestock Person-to-person transmission, though uncommon, can occur. CCHF virus is present in blood, body fluids and tissues of affected patients. Percutaneous or permucosal exposure to blood and other infected body fluids, especially blood, can result in secondary human spread. Hemorrhages are an important source of exposure for other people.  These factors increase the chances of nosocomial transmission of the diseases. There are several reports of nosocomial outbreaks in the hospitals following exploratory surgery on the patients.  The possibility of vertical transmission has also been reported. ,,
A common pathogenic feature of hemorrhagic fever viruses is their ability to disable the host immune response by attacking and manipulating the cells that initiate the antiviral response, characterized by marked replication of the virus together with dysregulation of the vascular system and lymphoid organs. The endothelium can be targeted in two ways: Indirectly by virus-mediated host-derived soluble factors that cause endothelial activations and dysfunction, and/or directly by virus infection and replication in endothelial cells. 
The incubation period depends on the mode of acquisition. It is usually 1 to 3 days, with a maximum of 9 days. ,, The incubation period following contact with infected blood or tissues is usually 5 to 6 days, with a documented maximum of 13 days. 
The main course of CCHF has been described as progression through four distinct phases of incubation, pre-hemorrhagic, hemorrhagic, and convalescence. , The onset of symptoms is sudden, with fever, chills, myalgia, dizziness, neck pain and stiffness, backache, headache, sore eyes and photophobia. There may be nausea, vomiting, and sore throat, which may be accompanied by diarrhoea and generalized abdominal pain.  After 2 to 4 days, the agitation may be replaced by sleepiness, depression and lassitude, and the abdominal pain may localize to the right upper quadrant, with detectable hepatomegaly. Other clinical signs are tachycardia, lymphadenopathy, and petechial rashes, both on internal mucosal surfaces, such as in the mouth and throat, and on the skin. The petechiae may give way to ecchymoses (like a petechial rash, but covering larger areas) and other hemorrhagic phenomena such as melaena (bleeding from the upper bowel, passed as altered blood in the feces), hematuria, epistaxis and bleeding from the gums. There is usually evidence of hepatitis and the severely ill patients may develop hepatorenal and pulmonary failure, after 5 th day of illness. ,
CCHF should be considered in those having:
Differential diagnoses should include rickettsiosis (tick borne typhus and African tick bite fever), leptospirosis, and borreliosis (relapsing fever). Additionally, other infections which present as hemorrhagic disease such as meningococcal infections, hantavirus hemorrhagic fever, Salmonella More Details, malaria, yellow fever, dengue, Omsk hemorrhagic fever, and Kyasanur Forest disease should be considered. , In Africa, Lassa fever and infection with the filoviruses, Ebola and Marburg, must also be included in the differential diagnosis. Some of the non-infectious diseases like Vitamin B12 deficiency and febrile neutropenia etc. can also present as hemorrhagic fever. 
The essential specimens to be submitted for virus isolation are a sample of venous blood (10 ml of clotted serum), a midstream ("clean catch") specimen of urine (5 ml), and a throat swab.  If postmortem specimens are to be taken then serum, liver, spleen, and kidney tissue are desirable. 
The confirmation of diagnosis of suspected CCHF is performed in specially equipped, high bio safety level laboratories (BSL-4) by following techniques:
Trends in disease occurrence
In endemic areas, poverty and social instability, , lack of vector control, insufficient medical equipment, and absence of infection control standards precautions contribute to the increased transmission.  The environmental changes like neglect of agricultural lands and subsequent agricultural and farming activity, and increase in wildlife populations are also known to increase the Hyalomma spp. tick population, and therefore increase the risk of exposure.  It has been argued that alteration in natural ecosystem, intensive agriculture, global warming and exponential increase in the movement of the people for any reason may have provided the possibility of expansion of this virus from endemic to neighboring to distant countries.  The other viruses like West Nile has followed the similar pattern and same might have happen to CCHFV.  The hypothesis says that global warming affects tick growth pattern and change bird migration also. Both of these factors affect the geographical distribution of the agent.
If clinicians feel that VHF is a likely diagnosis, they should immediately take two steps: Isolate the patient and notify local and state health departments.  The patient should be isolated in a single room with an adjoining anteroom serving as its only entrance. The anteroom should contain supplies for routine patient care, barrier nursing, hand-washing and containers of decontaminating solutions. If possible, the patient's room should be at negative air pressure and the air should not be re-circulated. Strict barrier-nursing techniques should be enforced. Isolation signs listing necessary precautions should be posted outside the anteroom. The patient should use a chemical toilet.
General supportive therapy is the mainstay of patient management in CCHF. Intensive monitoring to guide volume and blood component replacement is required. All secretions, excretions, other body fluids and all materials used in patient care should be treated with disinfectant solution. 
The disease surveillance system is also very important on detection of the suspected cases and their contact, where supervision of the contact is done till the maximum incubation period of 14 day. 
The antiviral drug Ribavirin is recommended in treatment of established CCHF infection. Ribavirin has been associated with high survival and early recovery. It has been recommended that treatment with Ribavirin should also be considered for suspected cases and post exposure prophylaxis for health care workers, potentially exposed to CCHFV.  Oral, intravenous and aerosolized ribavirin formulations can be used. Ribavirin preferably should be given intravenously for at least ten days, i.e., as a loading dose of 30 mg/kg followed by 16 mg/kg 6 hourly for four days and 8 mg/kg 8 hourly for another six days. For children, the use of oral or intravenous ribavirin has not been approved and only aerosolized Ribavirin has been approved.  In Kosovo, due to epidemiological situation and severity of the disease, Ribavirin (injection and tablet) was administered to the children also. 
It is not that use of Ribavirin is without controversies. The use of this drug for the case management of CCHF is under debate. There are limited numbers of studies on its beneficial effects and the results are variable. A recent review has concluded that use of Ribavirin is justifiable to continue to administer drug to suspected cases of CCHF. However, more studies are needed to prove efficacy.  The role of immune plasma, from recovered patients is doubtful, though it has been used on several occasions. ,,
Prognosis and outcome
The fatality rate from CCHF is approximately 30% (range 5-50%),  depending upon several factors, i.e., virus strain, day of diagnosis and treatment etc., with major proportion of deaths occurring in the second week of illness.  In patients who recover, improvement generally begins on the ninth or tenth day after the onset of illness. The convalescent phase is also seen; characterized by generalized weakness, weak pulse and tachycardia, sweating, dryness of the mouth, headache, dizziness, nausea, poor appetite, labored breathing, polyneuritis, poor vision, temporary loss of hair and hearing, and memory loss.  Recovery is usually complete but slow, and may take up to a year, and no relapse has been reported up to now. Therefore, there is no need for follow-up of cases. Health care workers exposed to the virus should be followed up with complete blood counts and biochemical tests for 14 days. 
Predictors of mortality
Researchers have described clinical laboratory criteria that could be measured early in the course of disease (during the first 5 days) and that predicted a fatal outcome.  These were: White blood cell count of 10×10 9 cells per L or above, platelet count of 20×10 9 per L or below, Aspartate Aminotransferase level of 200 U/L or over, Alanine Aminotransferase of 150 U/L or over, activated partial thromboplastin time of 60 seconds or more, or fibrinogen levels of 110 mg/dL or under Hematemesis, melena, somnolence and a little evidence of an antibody response were also the predictors of mortality. ,
Disease prevention and control
An inactivated, mouse brain derived, antigen preparation vaccine against CCHF has been developed and used on a small scale in Eastern Europe, specially in Bulgaria, but this vaccine is not widely available for human use. , The immunoglobulin products are also extensively used in Bulgaria but not in the other countries. A recent review has discussed about vaccines for CCHF prevention and other therapy. It provides detailed account and history of development of vaccine. The authors concluded that vaccine development for CCHF is severely hindered due to the absence of CCHF animal models. 
The tick vectors are numerous and widespread and tick control with Acaricides (chemicals intended to kill ticks) is only a realistic option for well-managed livestock production facilities. Persons living in endemic areas should use personal protective measures that include avoidance of areas, where tick vectors are abundant and when they are active, regular examination of clothing and skin for ticks, and their removal; and the use of repellents. In endemic areas, a measure of tick control has been achieved by environmental sanitation of underbrush habitats. Acaricides may be useful on domestic animals to control CCHFV-infected ticks, if used 10 to 14 days prior to slaughter or export of animals from enzootic regions. 
Persons who work with livestock or other animals in the endemic areas can take measures to protect themselves. These include the use of repellents on the skin (e.g., DEET) and clothing (e.g., permethrin) and wearing gloves or other protective clothing to prevent skin contact with infected tissue or blood. 
To reduce the risk of nosocomial spread of infection, when CCHF patients are admitted to hospital, it is imperative that adequate infection control measures are practiced. Patients with suspected or confirmed CCHF should be isolated and cared for using barrier nursing techniques. Specimens of blood or tissues taken for diagnostic purposes should be collected and handled using universal precautions. Sharps (needles and other penetrating surgical instruments) and body wastes should be safely disposed of using appropriate decontamination procedures. Healthcare workers who have had contact with tissue or blood from patients with suspected or confirmed CCHF should be followed up with daily temperature and symptom monitoring for at least 14 days after the putative exposure. 
Post-exposure prophylaxis should be considered potentially for those exposed to VHFs (including CCHFV) in a bioterrorism attack and all known high-risk individuals such as those who have mucous membrane contact (kissing or sexual contact with a patient) or have percutaneous injury in contact with the patients' secretions, excretions, or blood. Prophylaxis should also be considered with close contacts of the patients, and technicians who process laboratory specimens. They should be placed under medical surveillance and should be instructed to record their temperatures twice daily. If a temperature of 38.3° C or higher develops, treatment with ribavirin should be initiated promptly as presumptive treatment of CCHF. ,
Potential bioterrorism concerns
CCHFV can be transmitted from person to person with case-fatality rate in range of 5-50%. It may be transmissible by small-particle aerosol. The highly pathogenic nature of the CCHFV has led to the fear that it might be used as an agent of bioterrorism and/or bio-warfare. 
WHO has classified CCHFV is WHO risk group IV and suggests maximum bio-containment facility on research on this virus.  The requirement of BSL-4 has limited the number of researcher with access to pathogen. While CCHFV has been considered as a potential biological weapon,  this same factor is also preclude its development as a mass casualty weapon as argued by some other researchers.  Nonetheless, all possibilities need to be kept in the mind and research on it should be continued.
A suckling mouse brain, formalin-inactivated vaccine has been used in Bulgaria and other parts of Eastern Europe and the former Soviet Union. Dose required is 1 ml and initially two doses are to be given subcutaneously at an interval of four weeks. Re-vaccination is required at 1 year after the first vaccination and subsequently after every five years. ,, The efficacy had been successfully tested in 1,500 persons of Rostov region of the former Soviet Union and several hundred human volunteers in Bulgaria. , Effective antibody response is initiated 14 days after the vaccination. Also, with the relatively small target population of individuals at risk for contracting CCHFV, the large-scale development and production of a CCHF vaccine by modern standards seems unlikely. Moreover, divergence had been seen among the viral stains found in European, Asian and African region making the efficacy of Bulgarian vaccine doubtful in these regions. ,
No study that documents the socioeconomic impact of viral hemorrhagic fevers could be found even after extensive search. However, a study in Thailand assessed the disability-adjusted life years (DALYs) lost for fatal and nonfatal cases of dengue hemorrhagic fever, and indicated that dengue prevention, control and research should be considered as important as that of diseases currently given priority on the public health agenda.  International trade, tourism and animal get severely affected with outbreaks of viral hemorrhagic fevers and could result in significant economic losses especially in countries where animal resources constitute a significant source of national income.
Gujarat state of India reported cases of CCHF in January 2011  and the state had a tremendous breakdown along Ahmedabad district. The villages, where serious cases were reported were: Moraiya (13 suspected cases), Shela (6 cases), Changodhar (23 cases), Navapur-Vaghajipuar (13 cases), Dholeshwar (5 cases), Kolat (9 cases), Motidevti (1 case) and Telav (6 cases). CCHF had already claimed four lives in Ahmedabad.  There were 76 reported cases and 4 reported deaths. However, analysis of these cases will not be appropriate and will not provide correct interpretation as all cases were not confirmed and may not represent all cases and deaths in community.
As on February 10, 2011, entomologists had collected ticks from the affected village and Ahmadabad Municipal Corporation area and sent to National Institute of Virology (NIV), Pune, and High Security Animal Disease Laboratory in Bhopal, Madhya Pradesh. Rodent samples had also been sent to the laboratory in Bhopal. The virus (CCHF) has been found "in high quantities" in ticks collected from Ahmadabad. Scientists from the NIV (Pune) noted that the virus was now openly circulating in the environment and has not been brought into India from other CCHF endemic countries. 
National Centre for Disease Control, New Delhi has strengthened its capacity to test for CCHF virus. The polymerase chain reaction (PCR) primers have been developed and used for the testing of the samples. The Gujarat government had been equipped with stock of about 1,000 tablets of the drug Ribavirin. 
According to the WHO, CCHF virus has been present in India,  however, this is the first time a clinical case has been reported from India. The Director of NIV Pune commented that the effectiveness of Bulgarian CCHF vaccine is doubtful in India, and the shelf life of CCHF vaccine is longer, i.e., it can be preserved for up to 10 to 15 years, production and distribution of our own vaccine is a feasible option for pharma companies in India. So, Gujarat-based pharmaceutical companies will be allowed to produce the vaccine that is needed in the treatment of CCHF, in cooperation with the NIV. 
Gujarat's health department had started conducting surveillance post discovery CCHF cases in Ahmadabad city. Special teams were sent to the societies (where deceased lived) and hospitals (which had attended to CCHF patients) for surveillance of the residents, family members and the staff for unusual fever symptoms. 
In Kolat (block Sanand), a CCHF death was reported in an individual who had a small cattle farm. The animal husbandry department officials had conducted survey of livestock in villages within the vicinity of Kolat and reported no unusual cattle infection cases. A team of doctors and technicians surveyed villages within a radius of 5 kilometres of Kolat for individuals with symptoms of the viral fever. 
The outbreaks of VHF have become a regular phenomenon from the different parts of the world [Table 2]. Though, majority of these outbreaks have been reported from certain countries, the emergence of disease any new territories is always possible, if the country has the tick present in their setting [Table 2]. ,,,,,,, WHO already has a conducted the risk mapping of the countries [Figure 1].  The countries which have active agent present in their territories also need to have better preparation and surveillance mechanism for CCHFV.
Several public health challenges hinder the control of these outbreaks e.g. weak capacity of public health laboratories to confirm VHF, non-availability of bio-safety level 3 or 4 laboratory and of the necessary reagents and trained laboratory staff. The inadequate transparency in reporting due to the factors like delayed diagnosis, relatively weak epidemiological surveillance system, insufficient human capacity capable of analyzing data for evidence-based decision making, poor communication with the Ministry of Agriculture and other partners, and the concerns over negative economic repercussions. There is serious need to share experience between countries and make use of other global and regional resources through networking, publishing field experiences in bulletins and periodicals, and by holding scientific meetings. 
As per International Health Regulations of 2005, States/countries must notify WHO of all events that may constitute a public health emergency of international concern.  The countries are also obliged to report evidence of public health risks outside their territory that may cause international disease spread.
As VHFs have a potential to cause epidemics especially in the countries with limited resources, timely and appropriate response is essential. Experiences gained from the previous outbreaks and partnership at global level should be utilized for control of VHFs.  A few suggestions for prevention and control of VHF are: 
Although these steps appear to be simplistic, there are many unanswered questions to be debated by subject experts before countries march ahead on taking actions. The local expert should discuss that if developing countries like India with limited resources and high opportunity and resource cost should conduct surveillance for rare diseases like CCHF? Similarly, it needs to be answered whether the worst case scenario is always the right approach in public health? While the experts debate these questions globally, preparedness remains the key to prevention.
The presence of causative agent in many territories, along with the alterations in ecological patterns, natural evolution of invertebrate vectors, vertebrate hosts and viruses themselves, combined with rapid movement of people and animals on a global scale constantly generate conditions in which new viral pathogens emerge. However, with recent advances in scientific knowledge, the public health communities can be better prepared for these unexpected events. Timely detection of any pathogen during an epidemic always remains a public health challenge. The public health challenges are to generate awareness amongst public and clinician alike, ensure vector control options, maintain adequate surveillance systems with trained personnel, and to provide adequate case management. A fully integrated programme incorporating the advances in laboratory science with highly refined surveillance programs can help in combating the emerging threats of viral hemorrhagic fevers. It is time when nations take stock of emergence of these diseases to improve public health system in their own countries and address these heads on. The public health preparedness is the key to address the emerging and re-emerging diseases, which are becoming the reality of the times.
[Table 1], [Table 2]