Re-Evaluation of 400 Crimean-Congo Hemorrhagic Fever Cases in an Endemic Area: Is Ribavirin Treatment Suitable?

Abstract

Background:

Crimean-Congo hemorrhagic fever (CCHF) is a tick-borne viral disease, seen in various regions around the world, leading to death following a clinical syndrome of hemorrhagic fever.

Methods:

This trial was conducted in Tokat State Hospital that is located in an endemic area. Four hundred patients referring to hospital between 2007 and 2009 and diagnosed as having CCHF with RT-PCR were enrolled in this trial. Ribavirin was not administered to any patient. Epidemiological, clinical, and laboratory findings of CCHF and factors affecting mortality were evaluated.

Results:

Twenty patients (5%) died and 380 patients recovered (95%). It was found that mean age, white blood cells (WBC), active tromboplastine time (aPTT), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) values were significantly higher in patients who died, as compared with recovered cases and the difference was significant. Platelet values were significantly lower in patients who died, as compared with recovered cases.

Conclusions:

Age, male gender, high levels of ALT, AST, WBC aPTT values, platelet levels, and decrease in these values during follow-up are indicative of a poor prognosis. Use of ribavirin is not required in treatment of CCHF.

Introduction

C rimean-Congo hemorrhagic fever (CCHF) is caused by a Nairovirus which belongs to the genus Bunyavirus in the family Bunyaviridae (Drosten et al. 2002, Frangoulidis and Meyer 2005). CCHF is transmitted to humans by Hyalomma ticks or by direct contact with body fluids or tissues of infected humans or domestic animals (Khan et al. 1997, Izadi et al. 2004, Whitehouse 2004, Ergonul 2006).

CCHF, a potentially fatal viral infection, is seen in nearly 30 countries around the world. Currently, CCHF is a public health problem in many areas, namely Asia, Eastern Europe, Africa, and Russia (Ergonul et al. 2004). CCHF virus is known to cover the most extensive geographic range among tick-borne viruses with clinical significance in humans (Whitehouse 2004, Ergonul 2006).

Virus causes severe—usually fatal- disease in humans, with mortality rate reported as 5%–80% (Ertugrul and Uyar 2009). In Turkey, a rapid emergent increase was seen in CCHF cases since 2002 in central, northern, and eastern regions (Ergonul et al. 2004, Karti et al. 2004, Bakir et al. 2005). Mortality rates, reported by the Ministry of Health of Turkey, are 5% in 2002–2007 time period (Yilmaz et al. 2008), 4.79% in year 2008, and 4.77% in year 2009.

Endothelial cell damage is suggested as the main pathological mechanism responsible for CCHF, though pathogenesis is not clearly defined yet (Ergonul 2006).

Incubation period is followed by prehemorrhagic period, developing with a sudden onset during which fever, chills, severe headache, dizziness, photophobia, and back and abdominal pain are observed.

Initial characteristics indicating CCHF are clinical symptoms and patient history, especially recent travel to endemic areas and a history of tick bite or exposure to blood or tissues of infected livestock or humans (Whitehouse 2004). The most frequent clinical signs and symptoms of CCHF are fever, nausea, vomiting, loss of appetite, headache, back and abdominal pains, diarrhea, myalgia, petechial rash, and bleeding (Charrel et al. 2004). In most cases, fever is usually very high (39°C–41°C), progressing with steady high levels for 5–12 days or displaying a biphasic character (Whitehouse 2004).

Disease state is characterized by an increase in liver transaminases, leucopenia, and coagulopathy.

Diagnosis is based on isolation of virus in cell culture, serological methods (IFA, enzyme-linked immunosorbent assay), and RT-PCR (Whitehouse 2004).

Therapeutic options are limited in CCHF. There are several studies reporting experience on immunotherapy and ribavirin treatment with successful results (Vasilenko et al. 1990, Ergonul et al. 2004). In several trials, ribavirin is recommended for treatment of CCHF whereas in other trials, ribavirin treatment was shown to have no significant effect on mortality. Nevertheless, no case control study was conducted in this regard.

Tokat State Hospital is located in an endemic area for CCHF. In the current trial, epidemiological, clinical, and laboratory findings of the disease and factors affecting mortality were evaluated in 400 patients with CCHF.

Materials and Method

Patients and methods

Four hundred patients referring to Tokat State Hospital between years 2007 and 2010 with a definite diagnosis of CCHF were enrolled in this trial. While patients enrolled during 2010 were evaluated prospectively, other patients were assessed retrospectively.

Patients with tick-contact history and/or presenting clinical manifestations consistent with CCHF, who had white blood cell (WBC) <4500/mm³, platelet <150,000/mm³, alanine aminotransferase (ALT) >40 IU/mL, aspartate aminotransferase (AST) >40 IU/mL, and elongated prothrombine time (PT)-active tromboplastine time (aPTT) values, were hospitalized or followed up in the outpatient clinic settings by daily blood samples with their consents.

Cases whose blood samples were unavailable or cases that had no clinical and laboratory findings were excluded from the study.

Venous blood samples of patients were stored in optimal conditions and forwarded to Turkish MoH Refik Saydam National Hygiene Center for confirmation of diagnosis. Patients with positive PCR results for CCHF virus in blood samples were included in the study.

Places of living, age, gender, tick-contact history, and symptoms of patients were recorded in addition to hemogram, ALT, AST, PT, and aPTT values. Although hemogram, ALT, and AST values of patients were detected daily, PT and aPTT values were tested every other day. The lowest WBC and platelet values at application and during follow-up were recorded.

Supportive treatment was provided for all patients. If required, intensive care support was provided and blood and blood products were administered. Ribavirin was not administered to any patient.

Statistical analysis

Pearson's chi-square test was used to compare the categorical variables between groups. Categorical variables were presented as counts and percentages. The Kolmogorov–Smirnov test was used to evaluate whether the distribution of variables was normal. The two independent sample t test or Mann–Whitney U test was used to compare continuous variables between the two groups. Continuous variables were presented as mean (standard deviation) or as median (interquartile range). A p-value of less than 0.05 was considered to be statistically significant.

In order to define the lower limit of aPTT value, which affects the mortality rate, ROC analysis is performed. SPSS software 15.0 for Windows (Chicago, IL) was used for all statistical analysis.

Findings

Total participants were 400 patients; 222 males (54.5%) and 178 females (44.5%). Mean age was 47.11±17.22; it was observed that age is more advanced among patients with an outcome of exitus, as compared with recovered patients (p=0.006).

All patients were diagnosed with CCHF as a result of PCR, 45 patients were PCR and specific IgM positivities. Among patients with fatal outcomes, five patients were positive for both examinations.

Referral dates of patients accumulated in 5 months of the year, namely April, May, June, July, and August. Three hundred ninety-three patients were residing in a rural area. Among seven patients residing in urban areas, there was a history of travel to rural areas in all cases.

History of tick bite was present in 337 patients (84.2%) whereas 63 patients did not indicate such an experience (15.8%). Three out of 20 patients, who died, did not have any tick-contact history.

In family history of 4 patients (1%), a suspicion of CCHF and/or definite case of CHFF was present. Family history was not positive in any patient, apart from two couples (husband and wife) followed up with a diagnosis of CCHF.

Twenty-seven patients were followed up as outpatients (6.8%) whereas 363 patients were hospitalized (93.3%). Twenty patients (5%) died and 380 patients recovered (95%).

Referral symptoms of patients are shown in Table 1.

Table 1.

Inıtıal Symptoms of Patıents on Referral

Symptom/Sign N=400	Yes	No
Fever, N (%)	382 (95.5)	18 (4.5)
Asthenia, N (%)	297 (74.3)	103 (25.8)
Pain, N (%)	229 (57.2)	171 (42.8)
Nausea vomiting, N (%)	107 (26.8)	293 (73.3)
Anorrhexia, N (%)	89 (22.3)	311 (77.8)
Bleeding, N (%)	28 (7)	372 (93)
Diarrhea, N (%)	26 (6.5)	374 (93.5)

Pain was present in 230 patients (57.5%). Among patients with pain, headache was seen in 149 (37.3%), abdominal pain in 25 (6.3%), and generalized pain was present in 55 cases (13.8%).

Laboratory values of patients are shown in Table 2.

Table 2.

Laboratory Values of Patıents

	Patient (N=400)
Age, mean±SD	47±17
Male, N (%)	222 (54.5)
ALT, median (IQR)	45 (28–88.75)
AST, median (IQR)	77 (41–171.75)
WBC1, median (IQR)	2700 (2000–3800)
WBC2, median (IQR)	2200 (1600–3200)
Hemoglobin, median (IQR)	14 (12.7–14.9)
Platelet1, mean±SD	94±63
Platelet2, mean±SD	63±43
PT, median (IQR)	11.4 (10–13.15)
PTT, median (IQR)	37 (31–44)

AST, aspartate aminotransferase; ALT, alanine aminotransferase; WBC1, initial white blood cell count on referral; WBC2, lowest white blood cell count; platelet1, initial platelet value; platelet2, lowest platelet value; PT, prothrombine time; aPTT, active tromboplastine time; SD, standard deviation; IQR, interquartile range.

Values of recovered patients and patients in whom disease progressed to death were compared in Table 3.

Table 3.

Comparıson of Demographıc Characterıstıcs and Laboratory Values of Deceased and Recovered Patıents

	Recovered (N=380)	Exitus (N=20)	p-Value
Age, mean±SD	46 (18)	57 (8)	0.006
Male, N (%)	208 (55)	14 (70)	0.181
ALT, median (IQR)	43 (25.5–84)	74 (47–155)	0.001
AST, median (IQR)	73 (41–161)	199 (64–350)	0.002
WBC1, median (IQR)	2700 (2000–3600)	4150 (3700–4800)	0.002
WBC2, median (IQR)	2100 (1600–3000)	2750 (1500–4500)	0.473
Hemoglobin, mean±SD	13.7±1.64	12.64±3.39	0.963
Platelet1, mean±SD	98±48	65±40	0.000
Platelet2, mean±SD	63±42	14±8	0.000
PT, median (IQR)	11.15 (10–13)	13.1 (11–14.4)	0.035
PTT, median (IQR)	37 (31–43)	52 (47–65)	0.000

aPTT cut-off value was 46; with a sensitivity of 78% and specificity of 83%.

Discussion

This trial is invaluable because it had the highest number of patients enrolled in a CCHF trial up to this date. We believe that disease is encountered sporadically in different parts of the world, and since the numbers of patients are very low, the results do not completely represent CCHF disease. Thinking that studies with larger number of participants can demonstrate clearer information in evaluating the disease, data from 400 patients have been evaluated in this study.

Individuals residing in risky areas are prone to this disease, even though they may not refer with a history of tick bite. We believe that use of ribavirin is not required in treatment of CCHF.

Currently, CCHF is a public health issue in many regions around the world, including Asia, Eastern Europe, Africa, and Russia (Andersson et al. 2004). CCHF may present with different clinical disease states, varying from acute, self-limited conditions to progressive hemorrhagic fever with a fatal outcome (Cevik et al. 2008).

In Turkey, most cases were seen in northeast Anatolia (Tokat, Sivas, Gumushane, Amasya, Yozgat, and Corum provinces (Yilmaz et al. 2008). The location of our trial was Tokat, an endemic area for CCHF.

CCHF is a tick-borne zoonotic disease but it was shown that a contact with ticks may not be required for transmission. In trials conducted on adult patients in Turkey, history of tick contact was reported with a rate between 45% and 69% (Ozkurt et al. 2006, Yilmaz et al. 2008). In the current trial, history of tick contact was found to be 84.2%. In all patients, history of residing in or traveling to a rural area was determined. Results indicated that disease may be transmitted without a contact with ticks. It was striking to find no history of tick contact in 15% of fatal cases. This finding indicates that especially in rural areas, tick may leave the body before tick bite is discovered or virus may be transmitted through contact with infected materials. We may conclude that being in an area where ticks carrying virus are abundant is an important risk factor by itself, even though a history of tick contact may not be present.

Disease was not observed during the remaining months, apart from the 5 months indicated above. Seasonal characteristic of the disease should be considered during diagnosis.

In various trials, age was shown to present as a factor affecting mortality (Ozkurt et al. 2006, Tasdelen Fisgin et al. 2009). Similarly in this trial, it was found that mean age of patients who succumbed to disease were higher as compared with recovered patients and difference was regarded as significant.

In the current trial, the most frequently reported symptom was fever. Most frequent referral symptoms in this trial were fever, anorhexia, headache, abdominal pain and generalized myalgia, nausea and/or vomiting, diarrhea, and hemorrhage. Referral symptoms were compliant to symptoms reported in medical literature (Cevik et al. 2008).

Studies emphasize the fact that early diagnosis is important in terms of preventing transmission of disease (Whitehouse 2004). On the other hand, it was striking to find a positive family history in only 1% of our patients and no nasocomial CCHF infection during study period. We believe that this finding is due to the fact that transmission rate among humans is not as high as expected, all patients are isolated in terms of any contact and outpatients are informed with regards to transmission.

In various trials, mortality in CCHF was reported as 5%–80% (Schwarz et al. 1997, Frangoulidis and Meyer 2005). In Turkey, mortality rates of 0%–15.9% were reported (Ergonul et al. 2004, Cevik et al. 2008, Tezer et al. 2010). The case fatality rate reported by Ministry of Health of Turkey was 5% (Yilmaz et al. 2008). In the current trial, mortality rate was similar to Ministry of Health data (%5).

All of the patients, who applied to or internalized to our hospital have been included in this study. Forty-one patients, who have been referred to other healthcare units, have also been included into this study, by providing clinical data (recovery or exitus) from the Ministry of Health of Turkey. Therefore, we believe that, referrals of patients to other healthcare units have not affected the mortality rate. Since laboratory results of the referred patients could not have been obtained from the healthcare units, lowest values of WBC and PLT during their follow-ups could not have been recorded. However, values of WBC and PLT of these patients are recorded. Therefore, we believe that referral of these patients did not affect the mortality rate and baseline laboratory test results, but lowest white blood cell count and lowest platelet values have been affected by these referrals.

We believe that this discrepancy is due to patient characteristics of hospitals included in these trials. It may be concluded that in hospitals where patients with poorest prognosis are referred and treated in intensive care units, mortality rates are high whereas in centers like our hospital that are located in endemic areas and outpatients cases are treated in addition to hospitalized patients, rates are lower.

In severe cases, hemorrhagic manifestations were observed, ranging from petechia to extensive areas of ecchymosis (Whitehouse 2004). In the current trial, bleeding and/or ecchymosis were seen in 28 patients (7%). Since 12 (42.85%) out of 28 bleeding patients have been referred to other healthcare units, the rate of hemorrhage may be affected partially, but we believe that this has not caused a major difference in the results.

In clinical trials, it was shown that CCHF may lead to leucopenia and thrombocytopenia and these values may be used as criteria for poor prognosis. There are trials that indicate leukocytosis as criteria for poor prognosis whereas some trials do not support this view (Swanepoel et al. 1989, Ergonul et al. 2006, Cevik et al. 2008). Similarly in this trial, it was shown that leucopenia is seen in patients with CCHF, leukocytosis is observed with a higher rate in patients who died as compared with recovered patients and that the difference was significant. Again, platelet values were significantly lower in patients who died, as compared with recovered cases.

It was found that ALT and AST values were high, mean ALT and AST values were significantly higher in patients who died, as compared with recovered cases and the difference was significant.

Prolongation in PT and PTT values were shown in CCHF and this was considered as an important prognostic factor. Especially aPTT value of >60 s was determined in fatal cases (Ergonul et al. 2006, Onguru and Dagdas 2010). In the current trial, it was seen that PT was prolonged in fatal cases but difference between these levels and values of recovered cases was not significant. Significant increase in PTT values was observed in cases leading to death and significant difference was determined in these patients and between recovered cases (p<0.001). On the other hand, aPTT value of >60 indicated in several trials was not observed in our trial. Since aPTT value of >60 that is reported in several trials as an indicator of poor prognosis is not compliant with our results, we suggest that the lower limit of aPTT should be accepted as 46.

Therapeutic options in CCHF are limited. In experimental studies carried out in animal models, ribavirin was shown to inhibit replication of CCHF virus and it was indicated to be effective in Lassa and hanta virus infections (McCormick et al. 1986, Tignor and Hanham 1993). Nevertheless, its effectiveness in CCHF is controversial.

It is controversial that studies from Mardani et al. (2003) and Ergonul et al. (2008) have supported the use of ribavirin; Elaldi and Bodur (2009), Cevik et al. (2008), and Ozkurt et al. (2006) have reported that ribavirin use has no effects on mortality. Oral form of ribavirin with various side effects like hemolytic anemia, hypocalcemia, hypomagnesemia, acute respiratory symptoms, sinus bradycardia, end organ damage, hepatic, and renal failure is not recommended by Food and Drug Administration in CCHF cases but it's accepted as a potential therapeutic agent by World Health Organization (WHO) (Whitehouse 2004, Chiou et al. 2005). Ribavirin-induced anemia appears to result from the inhibition of the late stages of erythrocyte maturation in bone marrow and from the hemolysis of erythrocytes (American Society of Health-System Pharmacists 2003).

Elaldi and Bodur 2009 have reported that ribavirin might damage liver and renal functions and cause hemorrhage. Although intravenous (I.V.) form of ribavirin is recommended by WHO, we do not have this I.V. form in Turkey. Since there are no definite suggestions of CCHF treatment in the literature, we have not used ribavirin in this study.

Ribavirin is not recommended in patients with hepatic and renal failure (Sweetman and Martindale 2005). Ribavirin treatment was not initiated in any of the patients enrolled in this trial. In addition to supportive therapy, transfusion of blood products was provided, as needed. Results indicate that mortality rates are similar to values achieved in trials where ribavirin treatment was provided and hence, ribavirin treatment has no advantage in this regard.

Conclusion

In our area, CCHF remains to be an issue. CCHF should be considered in prediagnosis of every patient residing in risky areas and referring with fever, asthenia, and pain symptoms.

Disease is seen during spring and summer seasons.

Age, male gender, high levels of ALT, AST, WBC, aPTT values, platelet levels, and decrease in these values during follow-up are indicative of a poor prognosis. We believe that, ribavirin treatment is not required in the treatment of CCHF, but randomized controlled studies should be performed on this issue.

Footnotes

Disclosure Statement

No competing financial interests exist.

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