Investigation of the relation between thrombocyte counts and serum transaminases in patients with Crimean Congo hemorrhagic fever

Introduction

Crimean Congo hemorrhagic fever (CCHF) is potentially fatal zoonotic viral infection. It is mainly transmitted to humans by tick bite. Farmers, veterinarians, slaughters, people handling livestock and health care workers are the main groups at risk [1]. Turkey is the epicenter of worldwide CCHF activity. By December 2015 more than 9700 cases were recorded in Turkey [2]. Fever, thrombocytopenia and aminotransferase elevation are consistent features of CCHF. While thrombocyte count decreases, aminotransferases increase during the acute phase of infection [1]. In our country, since the serum for definite diagnosis of CCHF by nucleic acid amplification (PCR) or ELISA IgM should be sent to the reference laboratory immediate definite diagnosis is impossible. Clinicians should differentiate CCHF patients from other thrombocytopenic patients in the emergency setting through clinic and simple laboratory findings because CCHF requires rapid implementation of isolation precautions and consistent supportive therapy. In this study, to help physicians diagnose CCHF rapidly and accurately, the relation between thrombocyte count and transaminases were examined.

Materials and methods

All patients with confirmed CCHF who were hospitalized in Infectious Diseases Clinic of Gaziosmanpa University Hospital, Tokat, Turkey in 2015 were included in the study. Sera of patients were sent to the local virology reference laboratory of Public Health Agency of Turkey. Patients who had IgM antibodies to CCHF virus by ELISA or positive for CCHF virus RNA in blood by PCR were considered confirmed CCHF. Thrombocyte counts, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) test results of patients on admission and follow up days were obtained from medical records and used in the analysis. The patients were divided into three groups according to their first day thrombocyte counts. Group 1: thrombocyte <50,000/μL; group 2: thrombocyte: 50,000–100,000; group 3: thrombocyte >100,000/μL. The study was approved by the local Ethical Committee (Approval no: 17-KAEK-060).

Results

A total of 89 patients who had confirmed CCHF (57 males, 32 females) were included in our study. Mean age was 54.66±14.99 (range 23–81) years. Table 1 shows the results of correlation analysis between thrombocyte counts and AST, ALT levels at first day and the day at which patients reached the lowest thrombocyte count. According to first day thrombocyte count, 54 patients were in group 1, 20 in group 2 and 15 in group 3. When we assessed first day AST levels, only 9 (10.1%) patients had AST levels below the upper limit of normal (40 IU/mL) and all of these patients were in group 2 or 3. All group 1 patients had elevated AST levels at first day of hospitalization (Table 2). Medians of first day AST of patients in group 1, group 2 and group 3 were 325, 128, 71 IU/mL, respectively (Table 3). When we examined AST levels of patients in group 1 on subsequent days, no patient had normal AST levels. When we assessed first day ALT levels of patients, 70 patients had elevated ALT levels whereas 19 patients had ALT levels in normal range. All patients in group 1 except one had elevated ALT levels. On day 2, one patient in group 1 had normal ALT, but no patients had normal ALT levels on day 3 (Table 2). When the patients were categorized into two groups according to lowest thrombocyte count, those with thrombocyte count <50,000/μL and others with thrombocyte count >50,000/μL, concordant AST, ALT levels of all patients with thrombocyte count <50,000/μL were found to be above normal.

Discussion

Thrombocytopenia is a consistent feature of CCHF although it may not be observed through a few days after fever onset. A CCHF patient usually presents with fever, thrombocytopenia and elevated AST, ALT levels. Coagulation abnormalities may not be seen in nonsevere cases [1], [2], [3]. In this study we determined that there was strong correlation between thrombocyte counts and aminotransferases in CCHF and CCHF patients with thrombocytopenia (especially lower than 50,000/μL) almost always had elevated AST levels. This finding can be used in the differential diagnosis of a patient presenting with fever and thrombocytopenia in an emergency setting.

Several studies reported that higher levels of AST, ALT, creatine phosphokinase (CK), lactate dehydrogenase (LDH), international normalized ratio (INR), greater counts of white blood cell (WBC), lower counts of platelets and longer prothrombin time (PT) and activated partial tromboplastine time (aPTT) were found to be associated with fatality [4], [5], [6], [7]. In one of these studies, Hatipoglu et al. [4] emphasized that diarrhea, melena, hematemesis, hematuria, elevated ALT, LDH and prolonged aPTT were independent risk factors of fatality of CCHF. In the study of Yilmaz et al. [8] severity associated factors were determined based on clinical and laboratory findings on admission. CCHF patients were divided into severe and non severe cases according to whether they exhibited hemorrhage during hospital stay. Values above the predetermined cut-offs for INR, AST, C-reactive protein and platelet counts <90000/μL and, hemoglobin <13.5 g/dL were found to be associated with severity. An AST level of 117 U/L and an ALT level of 71 U/L were determined to be optimal cut-offs differing from severe cases to non-severe cases. Bakir et al. [5] suggested a severity grading score to predict fatality. This scoring system used laboratory parameters including AST, ALT, LDH, WBC and platelet count, PT, fibrinogen and D-dimer as well as some clinical findings on admission or during the first 5 days of hospitalization. It can be concluded that transaminase elevation is a consistent feature of CCHF and higher levels are associated with poor prognosis.

Knowledge about pathogenesis of CCHF is limited. Liver and spleen are the main sites of CCHF replication. Histopathologic studies showed that hepatocellular necrosis was the main finding ranging from mild necrosis to widespread damage of hepatic lobules [9], [10].

In this article we showed that CCHF patients with platelet counts lower than 50,000/mL should necessarily have AST values increased over normal values. This finding can be used in presumptive diagnosis of CCHF. CCHF may be confused with diseases that cause fever and thrombocytopenia. The list of differential diagnosis of CCHF includes bacterial, viral and noninfectious diseases. Bacterial diseases like brucellosis, Q fever, rickettsiosis, ehrlichiosis, Lyme disease, leptospirosis, salmonellosis and bacterial sepsis may overlap with CCHF. Malaria, tick-borne encephalitis, viral hepatitis, other bunyavirus infections such as Hantavirus infection, infections caused by arenaviridae, filovirideae and flavivirideae (yellow fever, dengue), may show similar clinical and laboratory features [1], [11]. Non-infectious diseases that should be considered in the differential diagnosis including Vitamin B12 deficiency, idiopathic and thrombotic thrombocytopenic purpura and hematologic malignancies [1], [12].

In the course of CCHF disease, as thrombocyte count decreases transaminases increase. Our study showed that, although transaminase elevation might not be seen in mild thrombocytopenic patients, it was the consistent finding of CCHF patients who had thrombocyte count <50,000/μL. According to our finding, when a patient with platelet count lower than 50,000/μL and normal AST and ALT levels applies to the emergency department, CCHF diagnosis can be ruled out. Thus, our finding is useful for diagnosing cases presenting with thrombocytopenia.