Early Use of Ribavirin Is Beneficial in Crimean-Congo Hemorrhagic Fever

Abstract

We evaluated the effect of early use of ribavirin on outcomes of patients at a secondary care hospital. The study included patients who were hospitalized between 2005 and 2010 at the Infectious Diseases Department of Kastamonu Dr. Münif İslamoğlu Hospital in the Kastamonu Province of Turkey. In total, 342 confirmed cases of Crimean–Congo hemorrhagic fever (CCHF) were included in the study. The overall case fatality rate was 2.9%. In multivariate analysis, the patients that were admitted to the hospital within 2 days after onset of symptoms (odds ratio [OR]=0.5, confidence interval [CI] 0.31–0.86) and received oral ribavirin (OR=0.12, CI 0.05–0.26) were less likely to become more severe cases and less likely to be transferred to the tertiary care centers. Having vaginal bleeding was a significant parameter for transfer.

Introduction

Crimean-Congo hemorrhagic fever (CCHF) is a fatal viral infection described from Africa, Asia, southeastern Europe, and the Middle East. The CCHF virus (CCHFV) belongs to the genus Nairovirus in the family Bunyaviridae and causes severe disease in humans, with a reported case fatality rate of 3–30%. Humans become infected through the bites of ticks, by contact with a patient with CCHF during the acute phase of infection, or by contact with blood or tissues from viremic livestock (Ergonul 2012). In addition to supportive therapy, ribavirin is the only antiviral drug that can be used in CCHFV infection and other viral hemorrhagic agents (Ergonul 2008, Bausch et al. 2010). There are controversial reports about the clinical effectiveness of ribavirin in treatment of CCHF at tertiary level. We evaluated the effect of early use of ribavirin on outcomes of the patients at a secondary care hospital.

Methods

This study included patients who were hospitalized between 2005 and 2010 at the Infectious Diseases Department of Kastamonu Dr. Münif İslamoğlu Hospital in the Kastamonu Province of Turkey. Severely ill patients were transferred to tertiary centers according to the regulations of Ministry of Health of Turkey. All of the cases were confirmed by CCHF immunoglobulin M (IgM) positivity and/or PCR RNA positivity. The patients that had onset of symptoms in less than 7 days and had no contraindications received ribavirin. Oral ribavirin was administered at the dosage recommended by the World Health Organization (4 grams once daily [q.d.] for 4 days, 2.4 grams q.d. for 6 days). According to a case management algorithm of the Ministry of Health of Turkey, patients older than 65 years old or severely ill patients were to be transferred to tertiary care centers. The severity criteria were defined as presence of rapid deterioration in clinical status, loss of consciousness, thrombocyte count less than 50,000/ mm³, prolonged activated partial thromboplastin time, and severe co-morbid conditions.

Statistical analysis was performed by STATA v. 11 (College Station, TX). Categorical comparisons were performed by a chi-squared test; if data were sparse, the Fisher test was used. Comparison of the means of continuous variables was tested by the Student t-test; the Kruskal–Wallis test was used for asymmetric distributions. Multivariate analysis was performed for the predictors of transfer of the patients.

Results

A total of 342 confirmed cases of CCHF were included in the study. Overall case fatality rate was 2.9%. The mean of days from tick bite to onset of symptoms and also from onset of symptoms to admission to hospital was longer in transferred group than nontransferred group (Table 1). The signs and symptoms, including vaginal bleeding, were more commonly observed among the transferred group (Table 1). Ribavirin use was less common, but case fatality rate was higher in the transferred group (Table 1). Laboratory records of 122 subjects are presented in Table 2. The patients that were transferred to tertiary centers had significantly lower platelet counts and elevated aspartate aminotransferase (AST) levels.

Table 1.

Demographic, Epidemiologic, Clinical, and Prognostic Characteristics of the Patients

	The patients who were transferred n=172 (%)	The patients who were not transferred n=170 (%)	p
Mean age	46 (SD 1.5)	52 (SD 1.4)	0.006
Age ≥60	52 (30)	76 (45)	0.006
Female gender	71 (41)	75 (44)	0.596
History of tick bite	120 (73)	134 (81)	0.067
Mean days from tick bite to onset of symptoms	4.1 (SD 0.13)	3.6 (0.14)	0.014
Living in rural area	148 (87)	162 (96)	0.001
History of close contacts with animals	134 (78)	156 (92)	<0.001
Mean days from onset of symptoms to admission to hospital	2 (SD 0.1)	1.7 (SD 0.1)	0.022
Fever	103 (60)	60 (35)	<0.001
Myalgia	144 (84)	125 (74)	0.021
Headache	124 (72)	92 (54)	0.001
Diarrhea	45 (26)	17 (10)	<0.001
Abdominal pain	66 (38)	31 (18)	<0.001
Rash	6 (3)	2 (1)	0.157
Bleeding	12 (7)	5 (3)	0.086
Vaginal	9 (5)	2 (1)	0.034
Gastrointestinal	4 (2)	2 (1)	0.418
Nasal	7 (4)	2 (1)	0.095
Gingival	3 (2)	0 (0)	0.084
Hematuria	8 (5)	4 (2)	0.248
Platelet <20,000/mm³	44 (26)	0 (0)	<0.001
Use of ribavirin	127 (74)	162 (95)	<0.001
Case fatality rate	10 (5.8)	0 (0)	0.001

SD, standard deviation.

Table 2.

Laboratory Findings of the Patients According to Their Status of Referral to Tertiary Care Centers

	The patients who were transferred n=58	The patients who were not transferred n=64	p
Median platelet count (×10³, min-max)	55 (6–135)	92.5 (59–149)	<0.001
Median leukocyte count (min-max)	1740 (510–11,300)	2100 (540–6500)	0.106
Median AST count (min-max)	146 (39–2344)	112 (25–442)	0.012
Median ALT count (min-max)	67.5 (14–1753)	92 (29–194)	0.329

AST, aspartate transaminase; ALT, alanine transaminase.

In multivariate analysis, the patients that were admitted to the hospital within 2 days after onset of symptoms (odds ratio [OR]=5, confidence interval [CI] 0.31–0.86) and received oral ribavirin (OR=0.12, CI 0.05–0.26) were less likely to become more severe cases and less likely to be transferred to tertiary care centers (Table 3). Having vaginal bleeding was a significant parameter for transfer.

Table 3.

Multivariate Analysis for the Predictors of Transfer of the Patients to Tertiary Care Centers

	Odds ratio	Confidence interval	p
Admission to the hospital within 2 days after onset of symptoms	0.5	0.31–0.86	0.012
Ribavirin use	0.12	0.05–0.26	<0.001
Vaginal bleeding	5.3	1.11–25.4	0.036

Discussion

Our results from a secondary care hospital clearly indicated that early use of oral ribavirin was beneficial for the patients (Table 3). Our results were not parallel with the results of another study that was published recently, in which the outcomes of 400 CCHF patients were followed at an epidemic center (Duygu et al. 2012). The authors did not administer oral ribavirin to CCHF patients, and they reported that a 5% fatality rate for CCHF could be acceptable. However, in our study, by using earlier ribavirin, the case fatality rate was 2.9%, and the patients that received ribavirin were less likely to be referred to tertiary care centers (OR=0.12, CI 0.05–0.26), which means their condition became less severe. Because both of these studies were performed in epidemic regions, the patients included in the studies have shorter duration from the onset of symptoms to admission than the patients included in studies at tertiary care centers. In the tertiary care center, ribavirin could be given about 4–5 days after the onset of symptoms (Cevik et al. 2008, Koksal et al. 2010). Some of the controversies about the effect of ribavirin arose from different timing of drug use and accordingly different severity of the symptoms (Ergonul 2009).

Ribavirin is still the only antiviral option in CCHF infection according to the studies performed in vitro (Paragas et al. 2004), in a knockout mouse model (Bente et al. 2010), and in some observational studies (Fisher-Hoch et al. 1995, Mardani et al. 2003, Ergonul et al. 2004, Ozkurt et al. 2005). The ribavirin could be more effective at the earlier and viremic phase of infection. Studies from Iran emphasized the prompt treatment with oral ribavirin for decreasing the case fatality among the patients with CCHF infection (Izadi and Salehi 2009, Sharifi-Mood et al. 2009).

The lack of randomization is the main criticism for these observational studies; however, performing a randomized clinical study is not possible because of ethical constrains (Arda et al. 2012). The observational studies could also give qualified information if they could be well designed and if the researchers would be aware of potential confounders (Ergonul 2009).

Conclusions

The patients that were admitted to the hospital within 2 days after onset of symptoms and received oral ribavirin were less likely to become more severe cases and accordingly less likely to be transferred to the tertiary care centers. Vaginal bleeding should be explored carefully, because it is a significant parameter of severity.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

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