Efficacy of high-dose methylprednisolone in patients with Crimean-Congo haemorrhagic fever and severe thrombocytopenia

Abstract

Crimean-Congo haemorrhagic fever (CCHF) is an acute viral haemorrhagic disease that is now endemic in south eastern Iran. The most important factor associated with mortality is a platelet count of less than 50,000/mL. The purpose of this study is to compare treated cases with severe thrombocytopenia using ribavirin with high-dose methylprednisolone (HDMP) with patients receiving ribavirin without HDMP. A clinical trial was conducted for confirmed patients with CCHF and severe thrombocytopenia (platelet count less than 50,000/mL) admitted to Boo-Ali Hospital in Zahedan between January 2010 and October 2011. The intervention group was given oral ribavirin, supportive managements and HDMP and the controls were treated with ribavirin and supportive management. Following HDMP therapy in hospitalized patients with severe thrombocytopenia, the platelet count increased within 36 h and the leukocyte count within 48 h of the beginning of treatment. Fewer in the intervention group required a transfusion of blood products than in the controls (P < 0.001). No one in the intervention group died. It seems that high-dose methylprednisolone is effective in the treatment of patients with CCHF. The increased platelet count and reduction of blood product requirement for severe CCHF patients after receiving HDMP are promising results. Further investigation is necessary in order to determine the efficacy of corticosteroid and its effect on outcome.

Keywords

CCHF methyl prednisolone ribavirin thrombocytopenia prednisolone Crimean-Congo haemorrhagic fever

Introduction

Crimean-Congo haemorrhagic fever (CCHF) is a viral haemorrhagic fever caused by the nairovirus which is a genus in the family of Bunyaviridae.¹ It is transmitted to humans by the bite of the Hyalomma tick or by direct contact with the blood of an infected animal or human.² It is an endemic disease in Iran, especially in the south eastern part of the country, and large outbreaks have occurred during the spring and summer seasons since 1999.³ CCHF is a severe disease with a high case fatality rate ranging from 2% to 70%.^3–5 Oral ribavirin is the most popular choice of therapy in our clinical practices.^6–10 If the patient meets the criteria for probable CCHF, the treatment with ribavirin needs to be started immediately.^6–7 Intensive monitoring in order to guide volume and blood component replacement is also recommended. Supportive therapy is an essential part of the case management.^1,2,6,7 Preventive measures, such as the use of histamine receptor blockers for prevention of peptic ulcer, avoidance of intramuscular injections and the use of aspirin and other anti-inflammatory drugs, are recommended.⁸ Fluid and electrolyte balance should also be carefully monitored. Replacement therapy with necessary blood products should be performed by checking the complete blood count, which must be done once or twice a day.^8–10 Despite the effect of ribavirin on the outcome of the disease, clinicians are sometimes faced with a high mortality rate during supportive therapy and treatment with ribavirin. Therefore, it is necessary to treat the patients with other regimens in order to reduce the mortality rate. Interferon has significant antiviral activity in vitro against many haemorrhagic viruses.¹¹ However, to our knowledge, no clinical studies have reported the efficacy of interferon against CCHF. The result of one study showed that prompt administration of CCHF hyper- immunoglobulin might be useful in the treatment of CCHF patients, especially for high-risk individuals.¹² Some reports revealed that fatal cases of CCHF received significantly more thrombocyte suspensions and fresh frozen plasma (FFP),^1,3,13–17 and that corticosteroid has a significant effect on raising the platelet count.¹⁶ In this study, we demonstrate the efficacy of high-dose methylprednisolone (HDMP) in patients with CCHF and severe thrombocytopenia.

Patients and methods

A clinical trial study was conducted at the Boo-Ali Hospital and Research Center for Infectious Diseases and Tropical Medicine in Zahedan (south eastern Iran, on the border of Afghanistan and Pakistan) between January 2010 and October 2011. All probable CCHF patients with severe thrombocytopenia (less than 50,000/mm³) were included in the study. Informed consent was taken from the patients and/or their family members immediately after admission. All patients received oral ribavirin and supportive therapy (platelet, FFP and erythrocyte suspension, depending on the laboratory test results). When the patients fitted the inclusion criteria, according to day of admission, treatment was initiated (on even days the intervention group was treated with ribavirin, necessary blood products and HDMP 10mg/kg as single dose for 3 days in the morning and then 5mg/kg for 2 days or more; on odd days the control group were treated without HDMP). The control group received only ribavirin and supportive care. Platelet counts were checked daily after the beginning of treatment in both groups. Confirmation of the disease was made by enzyme-linked immunoadsorbent assay (ELISA) and reverse transcriptase polymerase chain reaction (RT-PCR) in the Pasteur Institute of Iran that were reported to the centre 2–3 weeks later and 35 confirmed patients (13 cases and 22 controls) were entered into the final analysis. Confirmed cases were defined as probable cases with a positive serum RT-PCR test and/or positive immunoglobulin M (IgM) specific for CCHF by the ELISA method. Demographic and epidemiological data (age, sex, place of residence, tick bite and contact with animal products), clinical manifestations, the clinical course, the results of laboratory data, the amount of blood product requirement and the outcome were recorded for both cases and controls. Chi-squared, Fisher-exact and t-student tests were used for statistical analysis in order to compare qualitative and quantitative variables. A P value of <0.05 was considered to be statistically significant. The ethics committees of the Zahedan University of Medical Sciences in Iran approved the study protocol.

Results

Thirty-five patients with confirmed CCHF infection (28 men and 7 women within the age range 20–77 years) were evaluated. Thirteen of the intervention group were treated with ribavirin and HDMP and 22 controls with ribavirin without HDMP. All the patients were living in endemic areas for CCHF (Zahedan and Zabol, two large cities in the Sistan and Baluchestan provinces) and all had a history of animal contact. None had a history of tick bite within the previous 2 weeks. Thirty-three (94%) had fever, 29 (83%) headache, 23 (66%) myalgia and 22 (63%) complained of nausea and vomiting. Haemorrhagic complications, including epistaxis and subcutaneous haemorrhage – especially at the venepuncture sites – were observed in 13 (37%). There was no statistical significance between the two groups according to the demographic factors, clinical manifestations and outcome (Table 1). Augmentation of at least 10,000 platelet/mL was observed within 36 h and increased white blood cells (WBC) of at least 500/mL after 48 h following HDMP therapy. Of those who did not receive HDMP, only seven had an increased platelet count within 36 h and eight had an increased leukocyte count after 48 h. Cutaneous and visceral bleedings also improved faster in patients receiving HDMP. Blood product requirement in patients on HDMP therapy was less than those who were not receiving HDMP (P < 0.001; Table 2). No mortality was observed in the intervention group. Two of the patients in the control group died – they both had a platelet count of less than 10,000/mm³ on admission time (Table 1).

Table 1.

Demographic factors and clinical manifestations of patients with Crimean–Congo haemorrhagic fever in the intervention and control groups.

Characteristics	Intervention group (ribavirin + HDMP) n = 13 (100%)	Control group (ribavirin) n = 22 (100%)	P
Age (years; mean ± SD)	31.2 ± 7.4	32.9 ± 6.8	NS
Male	10 (77%)	18 (81.8%)	1.000
Living in rural area	3 (23%)	7 (32%)	0.709
Living in urban area	10 (77%)	15 (68%)	0.709
Fever	13 (100%)	20 (91%)	1.000
Headache	11 (85%)	18 (81%)	1.000
Myalgia	10 (77%)	13 (59%)	0.4632
Nausea and vomiting	8 (62%)	14 (63%)	1.000
Bleeding	5 (38%)	8 (36%)	0.901
Mortality	0 (0%)	2 (9%)	0.527

HDMP, high-dose methyl-prednisolone; SD, standard deviation; NS, not significant; WBC, white blood cell; FFP, fresh frozen plasma

Table 2.

Laboratory findings and blood products required during treatment of patients with Crimean–Congo haemorrhagic fever in the intervention and control groups.

Characteristics	Intervention group (ribavirin + HDMP) n = 13	Control group (ribavirin) n = 22	P
Lowest platelet count (/mL; mean ± SD)	19600 ± 6800	15000 ± 5400	NS
Lowest Hb (g/dL; mean ± SD)	11.1 ± 1.3	11.6 ± 1.7	NS
Lowest WBC count (/mL; mean ± SD)	3100 ± 1280	3700 ± 1650	NS
Increased platelet count 36 h after treatment	13	7	<0.001
Increased leukocyte count 48 h after treatment	13	8	<0.001
Total platelet suspension transfused	8 (60 Units)	21 (370 Units)	<0.001
Total erythrocyte suspension transfused	0	3 (20 units)	<0.001
Total FFP needed during treatment	3 (12 units)	12 (85 units)	<0.001

HDMP, high-dose methyl-prednisolone; Hb, haemoglobin; WBC, white blood cell; FFP, fresh frozen plasma; SD, standard deviation; NS, not significant

Discussion

CCHF is an acute, tick-borne viral disease that involves almost exclusively humans, often with severe haemorrhagic manifestations and a considerable mortality rate, especially when there is a known risk factor.^1,4,16 The first human cases of infectious haemorrhagic fever in Iran were reported from the western part of the country. Since June 1999, endemic areas for CCHF have substantially increased in several provinces of Iran with a high fatality rate (30%) in the first years.^1–4 Ribavirin is the only currently available promising therapeutic agent against CCHF. At the beginning of the epidemic in south eastern Iran we did not have enough information about the epidemiology of the disease in that area and ribavirin was not available for the treatment of CCHF patients. Therefore, the mortality rate was higher at that period. Using oral ribavirin immediately after the clinical diagnosis of patients had a significantly positive effect on patients’ survival.^1–4 Studies by Mardani (2003), Alavi-Naini and Metanat (2006) and Izadi (2009) revealed that the mortality rate was higher in untreated patients.^2,10,18,19 In the first study, between 1999–2004 in Sistan and Baluchestan, 165 confirmed cases were reported with a fatality rate of 22%.² In our study in 2009, the mortality rate was approximately 3%. Our results showed that oral ribavirin, especially when given at the beginning of the illness, had significant positive effect on the survival rate.⁴ In spring 2010 we were confronting a high mortality rate among patients with severe thrombocytopenia, despite prompt treatment with ribavirin and supportive therapy. The results of a study in Turkey showed that high-dose methylprednisolone had a good effect on raising the platelet count in severe thrombocytopenia in children.¹⁶ After treatment with HDMP, fever subsided and the platelet count increased in five children within 24 h. The leukocyte count also increased and visceral bleedings improved after starting methyl prednisolone. After starting HDMP, only one patient required blood products.¹⁶ In our study, after HDMP therapy in hospitalized patients with severe thrombocytopenia, platelet counts increased within 36 h. Cutaneous and visceral bleedings improved and leukocyte counts also began to increase within 48 h. Blood product requirement was significantly lower in patients receiving HDMP.

The pathogenesis of CCHF is not well understood. As in other viral haemorrhagic fever (VHF), CCHFV targets and impairs cells that begin the antiviral immune response. The pathogenesis of the disease could be a result of the direct injury of virus-infected tissues as well as the indirect effects of host immune responses such as cytokines. The correlation between viraemia levels and disease severity has not only been reported in patients with CCHF but also those with other VHFs such as dengue virus infection and in patients with haemorrhagic fever with renal syndrome.¹⁹ It is suggested that the presentations of CCHF could be a result of a delayed and down-regulated immune response caused by IL-10, which leads to an increased replication and spread of CCHFV throughout the body. The latter triggers increased production of gamma-interferon (IFN), alpha-tumour necrosis factors (TNF), cytokines mediating vascular dysfunction and disseminated intravascular coagulation.²⁰ However, corticosteroids inhibit cytokine, chemokine and adhesion molecule production and antagonize the action of pro-inflammatory cytokines, a hypothesis that seems to be a reasonable explanation for the improvement of those of our patients who received HDMP.

Conclusion

We suggest that HDMP, in addition to oral ribavirin and supportive management, may lead to clinical and laboratory improvements in CCHF patients with severe thrombocytopenia. Further double blind randomized clinical trials in different settings should be carried out in order to determine the timing and duration of HDMP treatment and its effect on outcome.

Footnotes

Acknowledgments

This article was extracted from a dissertation (registry code number 90-338 of irct.ir) which was financially supported by the deputy of research of the Zahedan University of Medical Sciences. We would like to thank all the staff of the ward of infectious diseases and the Zahedan Research Centre for Infectious Diseases and Tropical Medicine of the Boo-Ali Hospital.

Declaration of conflicting interests

None declared.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

References

Mardani

Keshtkar-Jahromi

. Crimean-Congo hemorrhagic fever. Arch Iran Med 2007; 10: 204–214.

Alavi-Naini

Moghtaderi

Koohpayeh

. Crimean-Congo hemorrhagic fever in southeast of Iran. J Infect 2006; 52: 378–382.

Sharifi-Mood

Mardani

Keshtkar-Jahromi

. Clinical and epidemiologic features of Crimean-Congo hemorrhagic fever among children and adolescents from South eastern Iran. Pediatr Infect Dis J 2008; 27: 561–563.

Sharifi-Mood

Metanat

Ghorbani-Vaghei

. The outcome of patients with Crimean-Congo hemorrhagic fever in Zahedan, southeast of Iran: a comparative study. Arch Iranian Med 2009; 12: 151–153.

Sharifi Mood

Mardani

Metanat

. Clinical manifestations, laboratory findings and clinical outcome in pregnant women with Crimean-Congo hemorrhagic fever. Iranian J Clin Infect Dis 2007; 2: 193–196.

Sheikh

. Ribavirin: an effective treatment of Crimean-Congo haemorrhagic fever. Pak J Med Sci 2004; 20: 201–206.

Sharifi-Mood

Alavi-Naini

Metanat

. Ribavirin: an effective drug for treatment of children with Crimean-Congo hemorrhagic fever. A seven-year experience. Pakistan J Bio Sci 2006; 9: 1898–1600.

Ergonul

Celikbas

Dokuzoguz

. Characteristics of patients with Crimean-Congo hemorrhagic fever in a recent outbreak in Turkey and impact of oral ribavirin therapy. Clin Infect Dis 2004; 39: 284–287.

Centers for Disease Control and Prevention. Viral hemorrhagic fever: Initial management of suspected and confirmed cases. MMWR Morb Mortal Wkly Rep 1983; 32(Suppl 2): 27–38.

10.

Mardani

Jahromi

Naieni

. The efficacy of oral ribavirin in the treatment of Crimean-Congo hemorrhagic fever in Iran. Clin Infect Dis 2003; 36: 1613–1618.

11.

Mirazimi

Old and new treatment strategies. In: Ergonul

Whitehouse

(eds). Crimean-Congo Hemorrhagic Fever: A Global Perspective, Dordrecht: Springer, 2007, pp. 258–260.

12.

Kubar

Haciomeroglu

Ozkul

. Administration of Crimean-Congo hemorrhagic fever (CCHF) virus hyperimmunoglobulin in Patients diagnosed with CCHF and viral load monitorization by reverse transcriptase-PCR. Jpn J Infect Dis 2011; 64: 439–443.

13.

Ozkurt

Kiki

Erol

. Crimean-Congo hemorrhagic fever in Eastern Turkey: clinical features, risk factors and efficacy of ribavirin therapy. J Infect 2006; 52: 207–215.

14.

Ergonul

Clinical and pathologic features of Crimean Congo hemorrhagic fever. In: Ergonul

Whitehouse

(eds). Crimean Congo Hemorrhagic Fever: A Global Perspective, Dordrecht: Springer, 2007, pp. 207–220.

15.

Pantanowitz L. Mechanisms of thrombocytopenia in tick-borne diseases. Internet J Infect Dis 2003; 2. http://www.ispub.com/ostia/index.php (last accessed on 18 October 2004).

16.

Dilber

Cakir

Erduran

. High-dose methylprednisolone in children with Crimean-Congo haemorrhagic fever. Trop Doct 2010; 40: 27–30.

17.

Metanat

Sharifi-Mood

Salehi

. Clinical outcomes in Crimean-Congo hemorrhagic fever: a five-year experience in the treatment of patients with oral ribavirin. Int J Virol 2006; 2: 21–24.

18.

Izadi

Salehi

. Evaluation of the efficacy of ribavirin therapy on survival of Crimean-Congo hemorrhagic fever patients: a case-control study. Jpn J Infect Dis 2009; 62: 11–15.

19.

Weber

Mirazimi

. Interferon and cytokine responses to Crimean Congo hemorrhagic fever virus; an emerging and neglected viral zonoosis. Cytokine Growth Factor Rev 2008; 19: 395–404.

20.

Saksida

Duh

Wraber

. Interacting roles of immune mechanisms and viral load in the pathogenesis of Crimean-Congo hemorrhagic fever. Clin Vaccine Immunol 2010; 17: 1086–1093.