1. Introduction
Crimean-Congo hemorrhagic fever (CCHF) is a tick-borne disease caused by a nairovirus (family Bunyaviridae). Crimean-Congo hemorrhagic fever virus (CCHFV) is endemic/enzootic in several countries in Africa, Asia, Europe, and the Middle East. The disease was first described in the Crimea in 1944 and given the name Crimean hemorrhagic fever. In 1969, it was recognized that the same pathogen was responsible for an illness identified in 1956 in the Congo; linkage of the two place names resulted in the current designation of Crimean-Congo hemorrhagic fever virus (CCHFV). CCHF patients may develop either a mild, nonspecific febrile syndrome or a more severe illness with vascular leak, hemorrhage and shock. Most cases occur sporadically, as a result of tick bite or direct contact with the blood or tissues of an infected animal.
2. Prevention of CCHF
Between 1969 and 1970, researchers of the Soviet Institute of Poliomyelitis and viral encephalitides developed an experimental vaccine based on brain tissue from CCHFV-infected newborn laboratory white mice and newborn albino rats. Brain tissue suspensions were inactivated by formaldehyde and heat treatment to obtain safe and noninfectious preparations. The vaccine did not have adverse affects on a limited number of humans who volunteered to be vaccinated with the preparation. Finally, in 1970, this inactivated anti-CCHF vaccine was approved by the Soviet Ministry of Health for CCHFV prophylaxis (1).
In 1974, this vaccine was licensed in Bulgaria and used in CCHFV-endemic parts of the country for persons over 16 years of age, such as military personnel or medical and agricultural workers. Recently published data from the Bulgarian Ministry of Health suggest a four-fold reduction in the number of reported CCHF cases over a 22-year time period (1953-1974: 1105 cases; 1975-1996: 279 cases) (2).
Modern vaccine development foresees the establishment of DNA vaccines, recombinant virus proteins-based vaccines, and virus-like particle (VLP) vaccines. For instance, American scientists have attempted to develop a CCHF DNA vaccine and tested its immunogenicity in mice. The DNA vaccine contained the entire M segment coding region of the CCHFV genome and elicited neutralizing antibodies in some of the vaccinated mice, as well as antibodies that co-immunoprecipitated the radiolabeled CCHFV M segment expression products (3).
3. Treatment
There is currently no specific treatment for CCHFV and therefore care of patients relies on active supportive clinical management, anti-CCHF hyperimmune sera, and the administration of ribavirin.
3.1. Ribavirin
The results of the available studies are at best confusing (Table 1, studies numbered 4-23) (4-23). There has been too much underlying variations in patient populations of different studies to draw any definite conclusion regarding the efficacy of ribavirin. It seems that treatment with ribavirin early in the course of infection may be beneficial. This approach to treating CCHF patients has been practiced in Middle Eastern countries for several years. A definite confirmation of ribavirin efficacy still requires better designed clinical trials, including studies with larger patient cohorts with matched controls in terms of confounding factors such as additional supportive treatments that can influence the disease outcome. One of the problems is the ethical issue regarding negative controls. On one hand, negative controls (i.e. untreated patients suffering from CCHF) are required to adequately judge the efficacy of a drug such as ribavirin in a patient cohort. On the other hand, CCHF is a readily fatal disease and it is clearly unethical to withhold a potentially effective treatment from an ailing patient. Additionally, CCHFV is a rather sporadic disease and larger outbreaks of the disease cannot easily be predicted. Setting up large clinical trials takes time and is logistically challenging. Designing them in the absence of knowledge regarding the whereabouts and extent of a CCHF outbreak is daunting. It is also unlikely that the burden of a larger, well-controlled and internationally acceptable CCHF clinical trial can be carried by a single country or region. A close interaction between all scientists in a CCHFV-endemic region with scientists all over the world and exchanging their expertise and resources would be most beneficial. However, whereas the bon mot “think globally not locally” sounds like a good summary on how to move forward one should not forget that numerous political and religious tensions exist among important countries that experience CCHF and those that could provide logistics, funding, and additional scientific expertise. How to uncouple humanitarian aid in crisis areas from global politics unfortunately remains an unsolved challenge and is one that must stand at the forefront of problems to be solved to control diseases such as CCHF.
In summary although there is no confirmation for the clinical efficacy of ribavirin, given the safety of short term ribavirin treatment and high case-fatality rate of CCHF, it is probably justifiable to initiate ribavirin treatment of all suspected cases in an endemic area until the accumulation of better (supporting or non-supporting) data for this particular treatment.
Table 1. Summary of Literature Published since 1985 until 2010 on the Efficacy of Ribavirin in CCHF
| Studies, No | Country | Number of Treated Cases/Total Number of Cases | Study Type | Ribavirin Used as Treatment or Prophylaxis | Reference |
|---|---|---|---|---|---|
| 1 | South Africa | 6/9 | Observational | Prophylaxis | (7) |
| 2 | Pakistan | 3/3 | Observational | Treatment | (4) |
| 3 | Pakistan | 2/2 | Observational | Treatment | (5) |
| 4 | Pakistan | 12/12 | Observational | Prophylaxis in 11 cases | (6) |
| 5 | Pakistan | 9/9 | Observational | Treatment | (8) |
| 6 | Iran | 6/6 | Observational | Treatment | (9) |
| 7 | Turkey | 10/10 | Observational | Treatment | (10) |
| 8 | Turkey | 235/281 | Observational | Treatment | (6) |
| 9 | Iran | 236/255 | Historical comparison | Treatment | (11) |
| 10 | Iran | 61/69 | Historical comparison | Treatment | (12) |
| 11 | Turkey | 22/60 | Historical comparison | Treatment | (13) |
| 12 | Turkey | 126/218 | Historical comparison | Treatment | (14) |
| 13 | Turkey | 8/30 | Non-randomized clinical trial | Treatment | (15) |
| 14 | Turkey | 9/25 | Non-randomized clinical trial | Treatment | (16) |
| 15 | Turkey | 41/52 | Non-randomized clinical trial | Treatment | (17) |
| 16 | Iran | 184/184 | Comparison to evaluate timing | Treatment | (18) |
| 17 | Iran | 63/63 | Comparison to evaluate timing | Treatment | (19) |
| 18 | Iran | 155/155 | Comparison to evaluate timing | Treatment | (20) |
| 19 | Turkey | 64/136 | Randomized clinical trial | Treatment | (21) |
3.2. Anti-CCHF Immunoglobulin
None of the studies described above have proven the efficacy of immune serum in post-exposure prophylaxis or treatment of CCHF. Just as in the case of ribavirin, immune sera have to be further evaluated in better designed clinical trials. For instance, one patient group could receive ribavirin and a control group could receive ribavirin plus immune sera. Ethical issues would not ensue as ribavirin would be administered to both groups. It seems that a collaborative study between countries that have enough supplies of immune sera, such as Bulgaria, and those that experience a higher incidence rate of CCHF (such as Turkey or Iran) could address the issue of efficacy of immune sera. A different way forward for countries with a higher incidence rate of CCHF would be to prepare large stocks of immune sera from affected patients and evaluate them during a subsequent outbreak.
3.3. Anti-CCHF Monoclonal Antibodies
Monoclonal antibodies were first used for CCHFV identification in 1987(24). Serum therapy for treatment or prophylaxis of CCHF has been used since 1964 (25). Scientists are now attempting to develop anti-CCHFV specific monoclonal antibodies (mAbs) for the treatment of patients. Monoclonal antibodies specific to both the CCHF Gn and Gc surface glycoproteins were generated to evaluate their neutralization and protective properties (26). It was concluded that neutralization of CCHFV depends not only on the properties of the used antibody, but also on host factors and non-neutralizing antibody-dependent mechanisms, such as antibody-dependent cell-mediated cytotoxicity.
3.4. Intravenous Immuneglobulin (IVIG)
There is little supporting the use of IVIG in treatment of patients with CCHF. In a recently published article from Iran, IVIG plus ribavirin were effective in reducing time to normalization of white blood cells (WBC), liver functions tests and platelet count in 12 patients compared to 28 patients who only received ribavirin. IVIG was not effective to reduce mortality which can be related to low number of cases in this study (22). In another study from Turkey, IVIG in association with high dose methylprednisolone was effective to decrease time to normalization of WBC, platelet count and D-dimer levels in 12 CCHF patients with reactive hemophagocytichistiocytosis (27). There is no more data available on this subject and more studies are needed for better evaluation.
3.5. Steroids
Role of high dose steroids has been studied in only one clinical trial in Iran(28), though it has been evaluated in other studies in Turkey (29). In the Iranian study, high dose methylprednisolone was tried in 13 patients with severe thrombocytopenia at presentation and results were compared to 22 patients with the same presentation. The result showed that treatment group had faster recovery in platelet and WBC counts compared to controls (28).
Both Iranian and Turkish studies showed better outcome and decreased mortality in patients with severe CCHF. These data support the usage of high dose corticosteroid in severely ill patients but more studies are needed to evaluate this effect better.
4. Summary
In conclusion, the only available and probably somewhat efficacious CCHF vaccine is an inactivated antigen preparation that is currently used in Bulgaria. DNA vaccines, recombinant CCHFV proteins, and CCHFV-like particles (VLPs) are promising candidates to be used in developing novel vaccines. However, given the overall scarcity of CCHF even in endemic countries it is questionable that large vaccination trials could be performed in human populations. This includes the problem of finding volunteers for vaccination, which is a task not to be easily neglected given the growing resistance of educated populations against using vaccines protecting them from dangerous and contagious diseases such as measles or poliomyelitis. Nobody has yet answered the question on how many people would have to be vaccinated and for how long they would have to be followed to conclude that a given vaccine is protective. Most scientists therefore believe in treatment rather than prophylaxis and think that ribavirin may be an effective treatment for CCHF, but some recently conducted and well-designed clinical trials counterprove this assumption. Immunoglobulin preparations (CCHF-bulin and CCHF-venin) have been used in Bulgaria for quite some time but no new data on these preparations have been published since 1990 and the confirmation of their efficacy requires additional studies. Current developments in antibody engineering have raised hopes for novel preventive and treatment strategies for CCHF, but there is currently no human monoclonal anti-CCHFV antibody available. At this point, all hopes for treatment depend on the development of two novel mouse models for CCHF. Immune sera, antibodies, ribavirin and more novel ways of treatment could at least theoretically be evaluated in these models and allow to draw some firm conclusions regarding their value.
