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Ribavirin is not effective against Crimean–Congo hemorrhagic fever: observations from the Turkish experience

  • Bahadır Ceylan
    Affiliations
    Faculty of Medicine, Department of Infectious Diseases and Clinical Microbiology, Bezmialem Vakıf University, Vatan Cad., Fatih 34093, Istanbul, Turkey
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  • Aylin Calıca
    Affiliations
    Faculty of Medicine, Department of Infectious Diseases and Clinical Microbiology, Bezmialem Vakıf University, Vatan Cad., Fatih 34093, Istanbul, Turkey
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  • Oznur Ak
    Affiliations
    Faculty of Medicine, Department of Infectious Diseases and Clinical Microbiology, Bezmialem Vakıf University, Vatan Cad., Fatih 34093, Istanbul, Turkey
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  • Yasemin Akkoyunlu
    Correspondence
    Corresponding author. Tel.: +90 530 143 65 55; fax: +90 212 621 75 80.
    Affiliations
    Faculty of Medicine, Department of Infectious Diseases and Clinical Microbiology, Bezmialem Vakıf University, Vatan Cad., Fatih 34093, Istanbul, Turkey
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  • Vedat Turhan
    Affiliations
    Faculty of Medicine, Department of Infectious Diseases and Clinical Microbiology, Bezmialem Vakıf University, Vatan Cad., Fatih 34093, Istanbul, Turkey
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Open AccessPublished:June 17, 2013DOI:https://doi.org/10.1016/j.ijid.2013.02.030

      Summary

      Crimean–Congo hemorrhagic fever (CCHF) is a viral infection associated with a high mortality rate. Ribavirin is the only drug used in the treatment of this disease. Studies investigating the effectiveness of ribavirin in CCHF have been retrospective and to date have included only a small number of cases. In recent years, due to climate changes, the number of cases of CCHF in Turkey has increased, and experience in the treatment of CCHF has improved. Several studies have evaluated the efficacy of ribavirin in Turkey, including one randomized controlled trial and two studies with a large number of cases. In these studies, ribavirin therapy was not shown to decrease mortality rates; the mortality rate was 2–9% in patients treated with ribavirin and 5.6–11% in those who were not treated with this drug. These findings suggest that patients with CCHF should be followed with supportive care only until randomized controlled trials with larger groups have been conducted.

      Keywords

      1. Introduction

      Crimean–Congo hemorrhagic fever (CCHF) is a viral infection seen in Asia, Europe, and the Middle East, and has a high mortality rate.
      • Ergonul O.
      Crimean-Congo haemorrhagic fever virus: new outbreaks, new discoveries.
      • Doganci L.
      New insights on the bleeding disorders in CCHF.
      CCHF is caused by a virus of the genus Nairovirus, family Bunyaviridae.
      • Ergonul O.
      Crimean-Congo haemorrhagic fever virus: new outbreaks, new discoveries.
      • Doganci L.
      New insights on the bleeding disorders in CCHF.
      The mortality rate is 3–30% and varies according to geographic area.
      • Ergonul O.
      Crimean-Congo haemorrhagic fever virus: new outbreaks, new discoveries.
      • Doganci L.
      New insights on the bleeding disorders in CCHF.
      The virus is usually transmitted to humans through tick bites or direct contact with the blood of an infected person during the acute phase of the disease.
      • Ergonul O.
      Crimean-Congo haemorrhagic fever virus: new outbreaks, new discoveries.
      • Doganci L.
      New insights on the bleeding disorders in CCHF.
      According to the World Health Organization, CCHF has been seen in 34 countries, and more than 50 cases are reported annually in four countries, including Turkey.
      • Chen J.P.
      • Cosgriff T.M.
      Haemorrhagic fever virus induced changes in hemostasis and vascular biology.
      The tropical climate zone is gradually expanding with the impact of global warming and this has enlarged the geographic area covered by the ticks that spread the disease.
      • Ergonul O.
      Crimean-Congo haemorrhagic fever virus: new outbreaks, new discoveries.
      The pathogenesis of this disease can be divided into three phases: pre-hemorrhagic phase, hemorrhagic phase, and convalescent phase.
      • Ergonul O.
      Crimean-Congo haemorrhagic fever virus: new outbreaks, new discoveries.
      • Doganci L.
      New insights on the bleeding disorders in CCHF.
      After transmission of the virus, it replicates and spreads through the bloodstream and causes flu-like symptoms lasting for 1 week (pre-hemorrhagic phase).
      • Ergonul O.
      Crimean-Congo haemorrhagic fever virus: new outbreaks, new discoveries.
      • Doganci L.
      New insights on the bleeding disorders in CCHF.
      After this stage, viral replication decreases, and macrophage-derived cytokines cause macrophage activation syndrome (hemorrhagic phase). During this second phase, death may occur due to hemophagocytosis and disseminated intravascular coagulation (DIC).
      • Ergonul O.
      Crimean-Congo haemorrhagic fever virus: new outbreaks, new discoveries.
      • Doganci L.
      New insights on the bleeding disorders in CCHF.
      Disorders of hemostasis are the most important features of CCHF. DIC is thought to occur via three mechanisms: increased release of tissue factor, direct injury, and the release of proinflammatory mediators.
      • Chen J.P.
      • Cosgriff T.M.
      Haemorrhagic fever virus induced changes in hemostasis and vascular biology.
      • Peters C.J.
      • Zaki S.R.
      Role of the endothelium in viral hemorrhagic fevers.
      • Ergonul O.
      • Tuncbilek S.
      • Baykam N.
      • Celikbas A.
      • Dokuzoguz B.
      Evaluation of serum levels of interleukin (IL)-6, IL-10, and tumor necrosis factor-alpha in patients with Crimean-Congo haemorrhagic fever.
      Increased synthesis of cell surface tissue factor activates the extrinsic coagulation pathway. A direct injurious effect on the endothelium and platelets occurs.
      • Chen J.P.
      • Cosgriff T.M.
      Haemorrhagic fever virus induced changes in hemostasis and vascular biology.
      • Peters C.J.
      • Zaki S.R.
      Role of the endothelium in viral hemorrhagic fevers.
      Proinflammatory mediators released from virus-infected monocytes lead to destruction of endothelial cells and platelets.
      • Ergonul O.
      • Tuncbilek S.
      • Baykam N.
      • Celikbas A.
      • Dokuzoguz B.
      Evaluation of serum levels of interleukin (IL)-6, IL-10, and tumor necrosis factor-alpha in patients with Crimean-Congo haemorrhagic fever.
      DIC presents as a decrease in clotting factors and platelets.
      • Ergonul O.
      Crimean-Congo haemorrhagic fever virus: new outbreaks, new discoveries.
      In addition, the liver dysfunction that occurs in the course of the disease contributes to a decrease in coagulation factors.
      • Ergonul O.
      Crimean-Congo haemorrhagic fever virus: new outbreaks, new discoveries.
      As a result of these events, massive bleeding can occur in CCHF.
      • Ergonul O.
      Crimean-Congo haemorrhagic fever virus: new outbreaks, new discoveries.

      2. Ribavirin treatment

      Although the main treatment option for CCHF is supportive therapy, ribavirin inhibits viral replication in vivo and has been shown to reduce death in murine models.
      • Keshtkar-Jahromi M.
      • Kuhn J.H.
      • Christova I.
      • Bradfute S.B.
      • Jahrling P.B.
      • Bavari S.
      Crimean-Congo haemorrhagic fever: current and future prospects of vaccines and therapies.
      Ribavirin is a guanosine analog with broad-spectrum antiviral activity.
      • Keshtkar-Jahromi M.
      • Kuhn J.H.
      • Christova I.
      • Bradfute S.B.
      • Jahrling P.B.
      • Bavari S.
      Crimean-Congo haemorrhagic fever: current and future prospects of vaccines and therapies.
      Until recently, studies supporting the use of ribavirin in CCHF have been retrospective, with a small number of cases.
      • Mardani M.
      • Keshtkar-Jahromi M.
      • Holakouie-Naieni K.
      • Zeinali M.
      The efficacy of oral ribavirin in the treatment of Crimean-Congo hemorrhagic fever in Iran.
      • Izadi S.
      • Salehi M.
      Evaluation of the efficacy of ribavirin therapy on survival of Crimean-Congo haemorrhagic fever patients: a case–control study.
      • Ozkurt Z.
      • Kiki I.
      • Erol S.
      • Erdem F.
      • Yilmaz N.
      • Parlak M.
      • et al.
      Crimean-Congo haemorrhagic fever in Eastern Turkey: clinical features, risk factors and efficacy of ribavirin therapy.
      • Elaldi N.
      • Bodur H.
      • Ascioglu S.
      • Celicbas A.
      • Ozkurt Z.
      • Vahaboglu H.
      • et al.
      Efficacy of oral ribavirin treatment in Crimean-Congo haemorrhagic fever: a quasi-experimental study from Turkey.
      • Bodur H.
      • Erbay A.
      • Akıncı E.
      • Öngürü P.
      • Bayazıt N.
      • Eren S.S.
      • et al.
      Effect of ribavirin treatment on the viral load and disease progression in Crimean-Congo hemorrhagic fever.
      • Tasdelen-Fisgin N.
      • Ergonul O.
      • Doganci L.
      • Tulek N.
      The role of ribavirin in the therapy of Crimean-Congo haemorrhagic fever: early use is promising.
      Important clinical questions are emerging due to the increasing number of patients in our country; also, ribavirin therapy is being evaluated for the treatment of CCHF. Ribavirin is the only antiviral drug used in CCHF and its effectiveness remains controversial.
      • Mardani M.
      • Keshtkar-Jahromi M.
      • Holakouie-Naieni K.
      • Zeinali M.
      The efficacy of oral ribavirin in the treatment of Crimean-Congo hemorrhagic fever in Iran.
      • Izadi S.
      • Salehi M.
      Evaluation of the efficacy of ribavirin therapy on survival of Crimean-Congo haemorrhagic fever patients: a case–control study.
      • Ozkurt Z.
      • Kiki I.
      • Erol S.
      • Erdem F.
      • Yilmaz N.
      • Parlak M.
      • et al.
      Crimean-Congo haemorrhagic fever in Eastern Turkey: clinical features, risk factors and efficacy of ribavirin therapy.
      • Elaldi N.
      • Bodur H.
      • Ascioglu S.
      • Celicbas A.
      • Ozkurt Z.
      • Vahaboglu H.
      • et al.
      Efficacy of oral ribavirin treatment in Crimean-Congo haemorrhagic fever: a quasi-experimental study from Turkey.
      • Bodur H.
      • Erbay A.
      • Akıncı E.
      • Öngürü P.
      • Bayazıt N.
      • Eren S.S.
      • et al.
      Effect of ribavirin treatment on the viral load and disease progression in Crimean-Congo hemorrhagic fever.
      • Tasdelen-Fisgin N.
      • Ergonul O.
      • Doganci L.
      • Tulek N.
      The role of ribavirin in the therapy of Crimean-Congo haemorrhagic fever: early use is promising.
      • Koksal I.
      • Yilmaz G.
      • Aksoy F.
      • Aydin H.
      • Yavuz I.
      • Iskender S.
      • et al.
      The efficacy of ribavirin in the treatment of Crimean-Congo haemorrhagic fever in Eastern Black Sea region in Turkey.
      Although some studies have suggested that the use of ribavirin is effective in CCHF, others suggest the opposite.
      • Mardani M.
      • Keshtkar-Jahromi M.
      • Holakouie-Naieni K.
      • Zeinali M.
      The efficacy of oral ribavirin in the treatment of Crimean-Congo hemorrhagic fever in Iran.
      • Izadi S.
      • Salehi M.
      Evaluation of the efficacy of ribavirin therapy on survival of Crimean-Congo haemorrhagic fever patients: a case–control study.
      • Ozkurt Z.
      • Kiki I.
      • Erol S.
      • Erdem F.
      • Yilmaz N.
      • Parlak M.
      • et al.
      Crimean-Congo haemorrhagic fever in Eastern Turkey: clinical features, risk factors and efficacy of ribavirin therapy.
      • Elaldi N.
      • Bodur H.
      • Ascioglu S.
      • Celicbas A.
      • Ozkurt Z.
      • Vahaboglu H.
      • et al.
      Efficacy of oral ribavirin treatment in Crimean-Congo haemorrhagic fever: a quasi-experimental study from Turkey.
      • Bodur H.
      • Erbay A.
      • Akıncı E.
      • Öngürü P.
      • Bayazıt N.
      • Eren S.S.
      • et al.
      Effect of ribavirin treatment on the viral load and disease progression in Crimean-Congo hemorrhagic fever.
      • Tasdelen-Fisgin N.
      • Ergonul O.
      • Doganci L.
      • Tulek N.
      The role of ribavirin in the therapy of Crimean-Congo haemorrhagic fever: early use is promising.
      • Koksal I.
      • Yilmaz G.
      • Aksoy F.
      • Aydin H.
      • Yavuz I.
      • Iskender S.
      • et al.
      The efficacy of ribavirin in the treatment of Crimean-Congo haemorrhagic fever in Eastern Black Sea region in Turkey.
      The most well-known study on ribavirin treatment was conducted in Iran by Mardani et al.
      • Mardani M.
      • Keshtkar-Jahromi M.
      • Holakouie-Naieni K.
      • Zeinali M.
      The efficacy of oral ribavirin in the treatment of Crimean-Congo hemorrhagic fever in Iran.
      In that study, eight of 69 patients treated with ribavirin died (11.6%), while seven of 12 patients who were not treated with ribavirin died (58.3%); this difference was statistically significant. However, the small number of cases in the control group and the retrospective design of the study may have decreased the reliability of the results. Mortality rates reported by Mardani et al. were higher than those in Turkey. This is because the CCHF strains in Turkey are different from those in Iran.
      • Ergonul O.
      Crimean-Congo haemorrhagic fever.
      In vivo studies have shown that different CCHF virus strains respond differently to ribavirin;
      • Watts D.M.
      • Ussery M.A.
      • Nash D.
      • Peters C.J.
      Inhibition of Crimean-Congo hemorrhagic fever viral infectivity yields in vitro by ribavirin.
      this may explain why patients did not respond well to ribavirin therapy in Iran.
      In contrast to studies in Iran, ribavirin therapy has not been shown to decrease the mortality rate in Turkey.
      • Ozkurt Z.
      • Kiki I.
      • Erol S.
      • Erdem F.
      • Yilmaz N.
      • Parlak M.
      • et al.
      Crimean-Congo haemorrhagic fever in Eastern Turkey: clinical features, risk factors and efficacy of ribavirin therapy.
      • Elaldi N.
      • Bodur H.
      • Ascioglu S.
      • Celicbas A.
      • Ozkurt Z.
      • Vahaboglu H.
      • et al.
      Efficacy of oral ribavirin treatment in Crimean-Congo haemorrhagic fever: a quasi-experimental study from Turkey.
      • Bodur H.
      • Erbay A.
      • Akıncı E.
      • Öngürü P.
      • Bayazıt N.
      • Eren S.S.
      • et al.
      Effect of ribavirin treatment on the viral load and disease progression in Crimean-Congo hemorrhagic fever.
      • Tasdelen-Fisgin N.
      • Ergonul O.
      • Doganci L.
      • Tulek N.
      The role of ribavirin in the therapy of Crimean-Congo haemorrhagic fever: early use is promising.
      • Koksal I.
      • Yilmaz G.
      • Aksoy F.
      • Aydin H.
      • Yavuz I.
      • Iskender S.
      • et al.
      The efficacy of ribavirin in the treatment of Crimean-Congo haemorrhagic fever in Eastern Black Sea region in Turkey.
      In these studies, the mortality rate was 2–9% in patients treated with ribavirin and 5.6–11% in patients who were not treated with ribavirin. There was no difference in terms of mortality, length of hospital stay, and transfusion of blood products among the patients treated and not treated with ribavirin.
      • Ozkurt Z.
      • Kiki I.
      • Erol S.
      • Erdem F.
      • Yilmaz N.
      • Parlak M.
      • et al.
      Crimean-Congo haemorrhagic fever in Eastern Turkey: clinical features, risk factors and efficacy of ribavirin therapy.
      • Elaldi N.
      • Bodur H.
      • Ascioglu S.
      • Celicbas A.
      • Ozkurt Z.
      • Vahaboglu H.
      • et al.
      Efficacy of oral ribavirin treatment in Crimean-Congo haemorrhagic fever: a quasi-experimental study from Turkey.
      • Bodur H.
      • Erbay A.
      • Akıncı E.
      • Öngürü P.
      • Bayazıt N.
      • Eren S.S.
      • et al.
      Effect of ribavirin treatment on the viral load and disease progression in Crimean-Congo hemorrhagic fever.
      • Koksal I.
      • Yilmaz G.
      • Aksoy F.
      • Aydin H.
      • Yavuz I.
      • Iskender S.
      • et al.
      The efficacy of ribavirin in the treatment of Crimean-Congo haemorrhagic fever in Eastern Black Sea region in Turkey.
      Studies of the effectiveness of ribavirin in CCHF were retrospective and included few cases.
      • Mardani M.
      • Keshtkar-Jahromi M.
      • Holakouie-Naieni K.
      • Zeinali M.
      The efficacy of oral ribavirin in the treatment of Crimean-Congo hemorrhagic fever in Iran.
      • Izadi S.
      • Salehi M.
      Evaluation of the efficacy of ribavirin therapy on survival of Crimean-Congo haemorrhagic fever patients: a case–control study.
      • Ozkurt Z.
      • Kiki I.
      • Erol S.
      • Erdem F.
      • Yilmaz N.
      • Parlak M.
      • et al.
      Crimean-Congo haemorrhagic fever in Eastern Turkey: clinical features, risk factors and efficacy of ribavirin therapy.
      • Elaldi N.
      • Bodur H.
      • Ascioglu S.
      • Celicbas A.
      • Ozkurt Z.
      • Vahaboglu H.
      • et al.
      Efficacy of oral ribavirin treatment in Crimean-Congo haemorrhagic fever: a quasi-experimental study from Turkey.
      • Bodur H.
      • Erbay A.
      • Akıncı E.
      • Öngürü P.
      • Bayazıt N.
      • Eren S.S.
      • et al.
      Effect of ribavirin treatment on the viral load and disease progression in Crimean-Congo hemorrhagic fever.
      • Tasdelen-Fisgin N.
      • Ergonul O.
      • Doganci L.
      • Tulek N.
      The role of ribavirin in the therapy of Crimean-Congo haemorrhagic fever: early use is promising.
      Therefore, determining the effectiveness of ribavirin in CCHF is problematic. Only one randomized controlled trial evaluating the efficacy of ribavirin has been performed in Turkey.
      • Koksal I.
      • Yilmaz G.
      • Aksoy F.
      • Aydin H.
      • Yavuz I.
      • Iskender S.
      • et al.
      The efficacy of ribavirin in the treatment of Crimean-Congo haemorrhagic fever in Eastern Black Sea region in Turkey.
      This study compared 64 patients given ribavirin and 72 without treatment. There was no significant difference in mortality rate, proportion of patients requiring platelet transfusion, length of hospital stay, recovery time, or laboratory parameters. Since 2002, when the first cases were reported in Turkey, the number of cases of CCHF has increased steadily. Two studies with a large number of cases showed no change in the course of disease with ribavirin treatment.
      • Duygu F.
      • Kaya T.
      • Baysan P.
      Re-evaluation of 400 Crimean-Congo hemorrhagic fever cases in an endemic area: is ribavirin treatment suitable?.

      Özcan MM, Elaldı N, Engin A, Korukluoğlu G, Dökmetaş I, Bakır M, et al. Oral ribavirin treatment of Crimean-Congo haemorrhagic fever: Kırım-Kongo hemorajik ateşinde oral ribavirin tedavisi: evaluation of 850 patients. 3rd Turkish EKMUD Congress, May 12–16, 2010. Ankara, Turkey. Congress Book; 2010, p. 204.

      Four hundred patients with CCHF confirmed by PCR were treated with supportive therapy.
      • Duygu F.
      • Kaya T.
      • Baysan P.
      Re-evaluation of 400 Crimean-Congo hemorrhagic fever cases in an endemic area: is ribavirin treatment suitable?.
      Twenty (5%) of these patients died. This mortality rate is similar to that of other studies of ribavirin for the treatment of CCHF in Turkey.
      • Ozkurt Z.
      • Kiki I.
      • Erol S.
      • Erdem F.
      • Yilmaz N.
      • Parlak M.
      • et al.
      Crimean-Congo haemorrhagic fever in Eastern Turkey: clinical features, risk factors and efficacy of ribavirin therapy.
      • Elaldi N.
      • Bodur H.
      • Ascioglu S.
      • Celicbas A.
      • Ozkurt Z.
      • Vahaboglu H.
      • et al.
      Efficacy of oral ribavirin treatment in Crimean-Congo haemorrhagic fever: a quasi-experimental study from Turkey.
      • Bodur H.
      • Erbay A.
      • Akıncı E.
      • Öngürü P.
      • Bayazıt N.
      • Eren S.S.
      • et al.
      Effect of ribavirin treatment on the viral load and disease progression in Crimean-Congo hemorrhagic fever.
      • Koksal I.
      • Yilmaz G.
      • Aksoy F.
      • Aydin H.
      • Yavuz I.
      • Iskender S.
      • et al.
      The efficacy of ribavirin in the treatment of Crimean-Congo haemorrhagic fever in Eastern Black Sea region in Turkey.
      In another study, the mortality rate of 336 patients taking ribavirin was 7.1% compared with 7% in 514 patients without treatment (p > 0.05).

      Özcan MM, Elaldı N, Engin A, Korukluoğlu G, Dökmetaş I, Bakır M, et al. Oral ribavirin treatment of Crimean-Congo haemorrhagic fever: Kırım-Kongo hemorajik ateşinde oral ribavirin tedavisi: evaluation of 850 patients. 3rd Turkish EKMUD Congress, May 12–16, 2010. Ankara, Turkey. Congress Book; 2010, p. 204.

      Other studies have suggested that ribavirin is not effective for the treatment of CCHF.
      • Ozkurt Z.
      • Kiki I.
      • Erol S.
      • Erdem F.
      • Yilmaz N.
      • Parlak M.
      • et al.
      Crimean-Congo haemorrhagic fever in Eastern Turkey: clinical features, risk factors and efficacy of ribavirin therapy.
      • Elaldi N.
      • Bodur H.
      • Ascioglu S.
      • Celicbas A.
      • Ozkurt Z.
      • Vahaboglu H.
      • et al.
      Efficacy of oral ribavirin treatment in Crimean-Congo haemorrhagic fever: a quasi-experimental study from Turkey.
      • Bodur H.
      • Erbay A.
      • Akıncı E.
      • Öngürü P.
      • Bayazıt N.
      • Eren S.S.
      • et al.
      Effect of ribavirin treatment on the viral load and disease progression in Crimean-Congo hemorrhagic fever.
      • Tasdelen-Fisgin N.
      • Ergonul O.
      • Doganci L.
      • Tulek N.
      The role of ribavirin in the therapy of Crimean-Congo haemorrhagic fever: early use is promising.
      • Koksal I.
      • Yilmaz G.
      • Aksoy F.
      • Aydin H.
      • Yavuz I.
      • Iskender S.
      • et al.
      The efficacy of ribavirin in the treatment of Crimean-Congo haemorrhagic fever in Eastern Black Sea region in Turkey.
      However, some researchers have considered ribavirin to be effective, especially when administered during the early period of the disease.
      • Izadi S.
      • Salehi M.
      Evaluation of the efficacy of ribavirin therapy on survival of Crimean-Congo haemorrhagic fever patients: a case–control study.
      Giving ribavirin to patients during the early and late periods of the disease produces different results. In one study that included a large number of cases, the mortality rate in patients who started ribavirin within the first 4 days after the onset of symptoms was no different to that of patients who started treatment later.
      • Elaldi N.
      • Bodur H.
      • Ascioglu S.
      • Celicbas A.
      • Ozkurt Z.
      • Vahaboglu H.
      • et al.
      Efficacy of oral ribavirin treatment in Crimean-Congo haemorrhagic fever: a quasi-experimental study from Turkey.
      In another study from Turkey, one of 21 patients treated during the first 4 days after the onset of symptoms died compared to two of 20 patients treated 4 days after the onset of symptoms; this difference was not significant.
      • Tasdelen-Fisgin N.
      • Ergonul O.
      • Doganci L.
      • Tulek N.
      The role of ribavirin in the therapy of Crimean-Congo haemorrhagic fever: early use is promising.
      In another study, the initiation of ribavirin in the first 4 days after the onset of symptoms was compared with starting treatment later and was shown to reduce mortality rates from 40% to 15.7% (p = 0.031).
      • Izadi S.
      • Salehi M.
      Evaluation of the efficacy of ribavirin therapy on survival of Crimean-Congo haemorrhagic fever patients: a case–control study.
      Again in this study, the mortality rate of patients receiving ribavirin before bleeding was lower than that of patients receiving ribavirin later (8% and 35.8%, respectively, p = 0.018). Reports that ribavirin is more effective during the first period of disease have also concluded that it decreases viral replication during the first week and so reduces the mortality rate. This hypothesis is supported by the fact that viral load is the most important factor contributing to mortality in CCHF.
      • Duh D.
      • Saksida A.
      • Petrovec M.
      • Ahmeti S.
      • Dedushaj I.
      • Panning M.
      • et al.
      Viral load as predictor of Crimean-Congo hemorrhagic fever outcome.
      However, a study from Turkey contradicts this hypothesis.
      • Bodur H.
      • Erbay A.
      • Akıncı E.
      • Öngürü P.
      • Bayazıt N.
      • Eren S.S.
      • et al.
      Effect of ribavirin treatment on the viral load and disease progression in Crimean-Congo hemorrhagic fever.
      In that study, 10 patients were given ribavirin and 40 were treated with supportive therapy. In the first 6 days of treatment, both viral load decline and mortality rates were similar in the two groups. In CCHF, viral load is important for determining the mortality rate, but ribavirin has not been shown to decrease viral load.
      An analysis of studies in Turkey between 2004 and 2007 has shown a gradual decrease in the use of ribavirin (67.9%, 21.8%, 16.2%, and 11.8%); despite this, mortality rates have not changed significantly (5.2%, 4.9%, 6.2%, and 4.6%, respectively) (Table 1).
      • Yilmaz G.R.
      • Buzgan T.
      • Irmak H.
      • Safran A.
      • Uzun R.
      • Cevik M.A.
      • et al.
      The epidemiology of Crimean-Congo hemorrhagic fever in Turkey, 2002–2007.
      This finding indicates the ineffectiveness of ribavirin.
      Table 1CCHF-related mortality rate and ribavirin use in Turkey, 2004–2007
      YearTotal number of CCHF patientsNumber of patients using ribavirinMortality rate
      2004249169 (67.9%)5.2%
      200526658 (21.8%)4.9%
      200643871 (16.2%)6.2%
      200771785 (11.8%)4.6%
      Although the efficacy of ribavirin in CCHF is highly controversial, its use is justified based on its being the only drug available. However, serious side effects are the major obstacle to this becoming a recommendation. In one study, 126 patients given ribavirin and 92 patients without treatment were followed; mortality rates did not differ. However, if only the first 8 days were considered, the mortality rate was 10.3 times higher in those receiving ribavirin.
      • Elaldi N.
      • Bodur H.
      • Ascioglu S.
      • Celicbas A.
      • Ozkurt Z.
      • Vahaboglu H.
      • et al.
      Efficacy of oral ribavirin treatment in Crimean-Congo haemorrhagic fever: a quasi-experimental study from Turkey.
      The increased mortality in that study was related to the toxic effects of ribavirin. In patients with a poor clinical course, ribavirin can increase the mortality rate due to severe organ damage. Similarly, in severe acute respiratory syndrome (SARS), patients with severe hypoxemia treated with ribavirin had a higher mortality rate due to the effects of the drug.
      • Chiou H.E.
      • Liu C.L.
      • Buttrey M.J.
      • Kuo H.P.
      • Liu H.W.
      • Kuo H.T.
      • et al.
      Adverse effects of ribavirin and outcome in severe acute respiratory syndrome: experience in two medical centers.
      Another obstacle to the use of ribavirin is its genotoxic effect.
      • Tatar A.
      • Ozkurt Z.
      • Kiki I.
      Genotoxic effect of ribavirin in patients with Crimean-Congo hemorrhagic fever.
      • D'Souza U.J.
      • Narayana K.
      Mechanism of cytotoxicity of ribavirin in the rat bone marrow and testis.
      • Narayana K.
      • D'Souza U.J.
      • Seetharama Rao K.P.
      Ribavirin-induced sperm shape abnormalities in Wistar rat.
      Ribavirin has been shown to have a mutagenic effect on lymphocytes and sperm.
      • D'Souza U.J.
      • Narayana K.
      Mechanism of cytotoxicity of ribavirin in the rat bone marrow and testis.
      • Narayana K.
      • D'Souza U.J.
      • Seetharama Rao K.P.
      Ribavirin-induced sperm shape abnormalities in Wistar rat.

      3. Conclusion

      All of these findings suggest that patients with CCHF should be followed with supportive care only until randomized controlled trials including larger populations have been conducted.

      Acknowledgement

      We would like to thank Prof. Dr Haluk Vahaboglu, who initiated debates on the problematic issues faced in the management of infectious diseases, including the use or not of ribavirin for the treatment of CCHF in Istanbul, Turkey.

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