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Hematological aspects of Crimean-Congo hemorrhagic fever/Kirim-Kongo kanamali atesinin hematolojik yonleri.

Epidemiology

Crimean-Congo hemorrhagic fever (CCHF) is an acute tick-borne viral disease that is transmitted to humans by Hyalomma ticks or by direct contact with the blood of infected humans or domestic animals. Nosocomial spread of infection mostly among healthcare personnel has also been reported. The causative virus is a member of the Nairovirus genus of the family Bunyaviridae and has a viral envelope [1-3]. Sporadic or endemic occurrence of the disease has been reported in some regions of Africa, Asia, southeastern Europe, and the Middle East. The estimated fatality rate is between 5% and 50%, reaching up to 72.2% in an outbreak in the United Arab Emirates [4-7]. Turkey is one of the countries where CCHF has occurred endemically in the spring and summer seasons of the past six years. The majority of cases were from the central northern and eastern regions of Turkey [8-15]. Between 2002 and 2007, 1820 cases with a confirmed diagnosis by enzyme-linked immunosorbent assay (ELISA) or polymerase chain reaction (PCR) were identified, and 92 of these died of the disease [8]. According to the most recent data published by the Turkish Ministry of Health for the period between 2002 and 2008, a total of 3135 cases were diagnosed with CCHF, and 155 (5%) of these died [9,10].

As its name implies, CCHF virus often results in severe hemorrhagic disease in humans, although not all patients develop the classic form of hemorrhagic disease. Viral load, acquisition route, and nature of host defense may play a major role in disease presentation. Nosocomial spread of infection carries higher risk than exposure through tick bite [5,6,16,17].

Clinical and Laboratory Findings

Clinically, CCHF consists of four phases, i.e. incubation, prehemorrhagic, hemorrhagic, and convalescence phases (Figure 1). The duration of the incubation period usually depends on the route of acquisition and extent of virus contamination. Following an incubation period of 3-7 days, the prehemorrhagic phase starts with acute-onset fever and nonspecific symptoms such as headache, photophobia, back and abdominal pain, myalgia, arthralgia, nausea, vomiting, and diarrhea. Fever generally subsides within 4-5 days but may persist up to 12 days. The hemorrhagic phase usually begins on the 4th-6th days of the disease, and during this phase, patients show signs of hemorrhagic diathesis ranging from mucocutaneous bleeding to fatal massive hemorrhage and disseminated intravascular coagulation (DIC). Bleeding symptoms may occur in 34 to 90% of the patients with CCHF. In addition to massive hemorrhage and hepatorenal failure, myocardial infarction, cardiorespiratory arrest and central nervous system dysfunction may develop with a fatal outcome. Laboratory findings of the disease include cytopenias (anemia and/or leukopenia and/or thrombocytopenia); elevated levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), creatinine phosphokinase (CPK), ferritin, bilirubin and fibrin degradation products; prolonged activated partial thromboplastin time (aPTT) and prothrombin time (PT); and decreased fibrinogen. It is noteworthy to mention that fibrinogen levels do not decrease in all cases since it is an acute phase reactant. For surviving patients, the convalescence period begins 15-20 days after the onset of disease. Weakness, weak pulse, sweating, dizziness and poor appetite have been reported in this period [2,5,6,12-18]. Hair, hearing or memory loss has also been reported in some patients [2,5,6]. Clinical and laboratory findings of CCHF are shown in Table 1.

Hematological Manifestations of CCHF Virus Infection

Epistaxis, gingival bleeding, petechiae, large ecchymoses, hematemesis, melena, hemoptysis with alveolar hemorrhage, hematuria, vaginal bleeding, and bleeding from venipuncture sites may occur due to thrombocytopenia and prolonged PT and aPTT in the hemorrhagic phase of CCHF [2,5,6,18-20]. Ocular findings with subconjunctival and retinal hemorrhage and without visual symptoms have also been reported in 73.7% of 19 patients [21]. Remarkably, a single patient was operated on the suspicion of acute appendicitis, but during the operation, hemorrhages in the oblique muscles and cecum were identified without any evidence of appendiceal pathology [22]. In severe cases with massive hemorrhage, DIC, intracranial bleeding, massive liver necrosis, and irreversible shock may develop, ultimately leading to death. The reported frequencies of hemorrhagic symptoms in fatal cases were 85% and 81.8% in the studies by Mardani et al. and Cevik et al., respectively [18,23]. Particularly, bleeding in the gastrointestinal and central nervous system is associated with a poor prognosis [23,24]. Hepatosplenomegaly was detected in approximately one-third of the patients with CCHF [2,3,5]. Hemophagocytosis was first reported in the study by Karti et al. [12] from Turkey, where half of the patients had this condition. Subsequently, other investigators also reported this important finding in CCHF [25,26], which is now considered to be associated with the development of cytopenia and poor prognosis [12,25]. In our view, routine use of bone marrow aspiration might yield a higher frequency of hemophagocytosis than the one reported in patients with CCHF. Cevik et al. [23] reported melena and hematemesis as the most common bleeding symptoms among fatal cases, with a particular emphasis on prolonged PTT (>60 sec) and low platelet count (<20000/[mm.sup.3]) as the most important risk factors for mortality. In addition, profound thrombocytopenia has been recognized as a poor prognostic sign by other investigators [2,5,23,24,27,28], and Tasdelen Fisgin et al. [27] found that 42% of patients with CCHF required transfusion of platelet suspensions. In a recent study by Ergonul et al. [24], hematemesis, melena, somnolence, low platelet count, prolonged PT and aPTT, and higher AST, ALT and fibrinogen levels were significantly more common among fatal cases compared to survivors. Similarly, Joubert et al. [16] found higher DIC scores in fatal cases. Decreased activity of thrombin- activatable fibrinolysis inhibitor (TAFI) was present in patients with CCHF and was attributed to the imbalance in fibrinolysis and DIC [29]. In another study from Turkey, increased natural killer (NK) cell counts were observed in CCHF patients, and this finding was correlated with abnormalities in AST/ALT and aPTT [30]. In another study, cytotoxic T lymphocyte (CD8) counts were increased [31].

[FIGURE 1 OMITTED]

Pathogenesis

The basic pathogenesis of CCHF at the molecular level is complex and not well defined. Endothelial cells, immune response, viral load, and coagulation cascade play important roles in the disease pathogenesis. Blood and endothelium appear to be the target tissues of the disease. Marked viral replication results in severe viremia during the first two phases of the disease. On the other hand, inappropriately activated T helper 1 (CD4 Th1) lymphocytes produce tumor necrosis factor-[alpha](TNF-[alpha]) and interferon gamma (IFN[gamma]), which promote macrophage co-activation and oversecretion of interleukin-1 (IL-1) and IL-6. The endothelium is directly infected by the virus and/ or damaged by secreted cytokines that stimulate the production of some vasodilator substances, platelet aggregation, and activation of coagulant proteins. Activation of coagulation may contribute to the development of DIC and multiorgan failure [1,5,6,12,15,18,23,24,28]. Following macrophage activation and profound cytokine secretion, hemophagocytosis may occur in various infectious diseases including CCHF. Hemophagocytosis is an important clinical entity, which is presumed to be associated with cytopenia and increased risk of mortality [12,25,27,28,32-34]. Papa et al. [35] and Ergonul et al. [36] reported increased levels of TNF-[alpha], IL-1, and IL-6 in patients with CCHF. They also found significantly higher TNF-[alpha] and IL-6 levels in fatal cases as compared to mild cases, emphasizing the pivotal role of the cytokine storm in the pathogenesis of CCHF [35-38]. Ongoru et al. [39] showed high serum neopterin levels in CCHF and its increment correlated with mortality from the disease. Since neopterin is produced by activated macrophages upon secretion of IFN[gamma], their findings may be considered as a further piece of evidence supporting the important role of cytokine secretion and macrophage activation in the pathogenesis of CCHF. Oversecretion of IL-18-induced Fas ligand expression on lymphocytes may contribute to the cytotoxicity of Fas-expressing hepatocytes, which might be responsible for hepatic failure and bleeding in secondary hemophagocytosis [40,41]. A similar mechanism might also be relevant in patients with CCHF. Extremely increased ferritin levels were reported in patients with CCHF virus infection [27,28], and this has been accepted among the diagnostic criteria for primary hemophagocytic lymphohistiocytosis (HLH) [42].

Our Experience

The facilities of our university are located in the Black Sea region of Turkey, which is close to the area endemic for CCHF. To date, 164 cases, most of whom were adults, have been diagnosed and followed in our hospital [14,25,27,47]. Between 2004 and 2006, we diagnosed and followed nine children with CCHF. The age rage was between 2 and 16 years, and their initial clinical and laboratory findings were as follows: fever and fatigue were present in all nine patients; nausea, vomiting, and petechial rash were present in eight, hematemesis and melena in five, and epistaxis in two. One patient presented with hemoptysis, somnolence and convulsions. Two patients had hepatomegaly and one had splenomegaly. Laboratory findings included anemia (Hb: 4.5-10 g/dl) and leukopenia (WBC counts: 1400-3900/[mm.sup.3]) in five and thrombocytopenia (platelet count: 5000-36000/[mm.sup.3]) in seven children. Elevated levels of AST (105-2852 U/L), ALT (372-3100 U/L), LDH (912-5100 U/L) and CPK (297-2900 U/L) were present in eight, seven, eight, and six patients, respectively. Prolonged PT (16-32 sec) and aPTT (54-140 sec) were detected in four and seven cases, respectively. Increased D-dimer (609-1430 U/L) was found in seven children. Bone marrow aspiration was performed in three children and significant hemophagocytosis was determined in all of these cases. With a presumptive diagnosis of CCHF, ribavirin therapy and supportive measures including the administration of fresh frozen plasma (FFP) and/or packed red cells and/or platelet suspensions were initiated until the diagnosis was confirmed with ELISA or PCR. Full recovery was obtained in all children without any complication [25,43].

Diagnosis and Treatment

Early diagnosis is very important with regard to the outcome in CCHF. Patients with clinical and laboratory findings of CCHF and history of tick bite or exposure to infection should be tested for CCHF. Laboratory methods include virus isolation and serologic and molecular assays with reverse transcription PCR or real time PCR. Antibodies are detectable in the serum by ELISA or immunofluorescence assay (IFA) about seven days after the onset of disease. Antibodies are not detectable in fatal cases who die within the first days of illness. Molecular studies are necessary for confirmation of the disease in such cases [1,2,5,44,45].

There are three principal and equally important objectives in the treatment of CCHF: close monitoring of all coagulation parameters, supportive treatment with FFP, erythrocyte and platelet suspension, and early antiviral treatment [1,5,6,46].

Continuous evaluation of clinical status, including vital organ functions and observation of bleeding, are mandatory for patients with CCHF. Supportive treatment should be provided with FFP and erythrocyte and platelet suspensions. Close monitoring of platelet count, fibrinogen and D-dimer levels is important for early detection of DIC, which also allows early correction of coagulation parameters. Ergonul et al. [1] reported a higher requirement for platelet suspensions in cases with a fatal outcome. If available, apheresis of platelet suspensions that provide a large amount of platelet content (3 x [10.sup.11]/per apheresis platelet suspension) should be preferred. Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit blood clotting and cause an increased risk of bleeding; therefore, they should not be used in CCHF. FFP transfusion is indicated for the correction of coagulopathy in bleeding or for the prevention of bleeding in CCHF. When PT and aPTT are at least 1.5 times greater than the upper limit of the normal range or international normalized ratio (INR) is >1.6, FFP (15-20 ml/ kg) should be given, and this treatment should be repeated every 8-12 hours, if necessary. In addition to these supportive measures, unfractionated or low molecular weight heparin, recombinant human activated protein C, recombinant activated factor VII, and antifibrinolytic agents should also be considered in CCHF patients with uncontrolled bleeding and DIC [1,5,6,12,14,18,46].

Although the effect of ribavirin treatment in CCHF virus infection has not been proven in randomized prospective clinical trials, and there are some conflicting results in the clinical reports, however majority of them indicate its beneficial effects (11,15,46-49). Based on these reports, ribavirin seems to be widely accepted in the treatment of CCHF and its use is recommended especially in the early phase of the disease [11,15,46-48].

Secondary hemophagocytosis may resolve upon the treatment of underlying disease, although it may be as fatal as primary HLH [32,33]. A genetic mutation is responsible for the impaired antiviral defense, dysregulated immune response and insufficient lymphocytic apoptosis in primary HLH [32,33,42,50]. A protocol consisting of dexamethasone, cyclosporine A and etoposide has been widely accepted in the treatment of patients with primary HLH [42]. This was also shown to be beneficial in the treatment of Epstein-Barr virus-associated HLH [51,52]. Although a genetically transmitted dysregulated immune response occurs in the above-mentioned HLHs, which are completely distinct from secondary hemophagocytoses including CCHF, these entities share some common clinical and laboratory features, most of which are mediated via the same mechanisms. Uncontrolled CD4 Th1 activation and overproduction of proinflammatory cytokines with macrophage coactivation-induced hemophagocytosis are well established in all types of HLH [32,33,42,50-52]. Pathogen-directed therapy might not always be sufficient to control cytokine storm in secondary hemophagocytoses including the one associated with CCHF. Although immunosuppression is known to exacerbate the spread of infections, use of immunosuppressive therapy along with ribavirin might be considered in the treatment of the patients with CCHF who have uncontrolled hemophagocytosis and severe bleeding symptoms. Jabbari et al. [53] reported a complete recovery in six patients with CCHF who received corticosteroids combined with ribavirin in the early phase of the disease. Similarly, cyclosporin and/or etoposide with or without steroids successfully controlled excessive activation of lymphocytes/monocytes and oversecretion of cytokines in various infection-associated HLHs [52-59].

New treatment strategies such as IFN or antibodies against TNF or IL-6 could prove to be valuable in CCHF [38], but the experience is limited, and further studies are warranted. Obviously, the timing of these therapeutic approaches should also carry a significant importance.

It is our hope that an effective immunization strategy with a safe vaccine and/or specific serum against CCHF virus will soon be in use in order to overcome this frequently fatal disease.

No author of this paper has a conflict of interest, including specific financial interests, relationships, and/or affiliations relevant to the subject matter or materials included in this manuscript.

Received: May 11, 2009 Accepted: August 4, 2009

Gelis tarihi: 11 Mayis 2009 Kabul tarihi: 4 Agustos 2009

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Feride Duru, Tunc Fisgin

Department of Pediatric Hematology, Ondokuz Mayis University, Faculty of Medicine, Samsun, Turkey

Address for Correspondence: Prof. Dr. Feride Duru, Ondokuz Mayis University Faculty of Medicine, Department of Pediatric Hematology, Kurupelit 55200 Samsun, Turkey Phone: +90 362 312 19 19 / 30 99 E-mail: ferideduru@superonline.com
Table 1. Clinical and laboratory findings of CCHF (1,5,6,12,14,18-25,
28-30,37)

Clinical Findings Laboratory Findings

Cardiovascular System Biochemical
 Bradycardia Elevated AST, ALT
 Low blood pressure Elevated lactate dehydrogenase
 Heart murmur Elevated creative kinase
 Myocardial infarction Hyperferritinemia
 Cardiorespiratory arrest Hypertriglyceridemia

Respiratory System Hematological
 Cough, rates, tachypnea Anemia
 Pleural effusion Leukopenia, leukocytosis
 Acute respiratory distress
 syndrome Thrombocytopenia
 Diffuse alveolar hemorrhage Prolonged PT, aPTT
 Decreased fibrinogen
 Elevated D-dimer

Skin Immunological
 Jaundice, hair loss Increased levels of cytokines
 (TNF[alpha], IL-1 ,IL-6, IL-10)
 Increased serum neopterin
 Increased absolute number of
 peripheral blood natural killer
 cells

Gastrointestinal System
 Hepatomegaly, splenomegaly
 Abdominal tenderness

Central Nervous System
 Polyneuritis, headache
 Somnolence, lethargy
 Loss of hearing, poor vision
 Loss of memory

Hematological Findings and Bleeding Symptoms:
 Petechia, ecchymoses
 Hematemesis, melena
 Gingival bleeding, epistaxis
 Bloody otorrhea
 Subconjunctival and/or retinal hemorrhage
 Hematuria
 Vaginal bleeding
 Hemoptysis
 Diffuse alveolar hemorrhage
 Intracerebral hemorrhage
 Hemophagocytosis
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Author:Duru, Feride; Fisgin, Tunc
Publication:Turkish Journal of Hematology
Article Type:Report
Geographic Code:7TURK
Date:Dec 1, 2009
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