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RESEARCH ARTICLE
Year : 2022 | Volume
: 59
| Issue : 2 | Page : 163-171
Role of TGF-β1 and PDGF-B in Crimean-Congo hemorrhagic fever in Eastern Anatolia Region in Turkey
Nazan Cinislioglu1, Halil İ Özkan2, Seda Aşkın2, Sinan Yılmaz3, Ahmet Kızıltunç2, Kemalettin Özden4
1 Department of Infections Diseases and Clinical Microbiology, University of Health Sciences Erzurum Regional Training and Research Hospital, 25040, Palandöken, Erzurum, Turkey
2 Department of Biochemistry, Ataturk University Faculty of Medicine, Erzurum, Turkey
3 Department of Public Health, Ataturk University Faculty of Medicine, Erzurum, Turkey
4 Department of Infections Diseases and Clinical Microbiology, Ataturk University Faculty of Medicine, Erzurum, Turkey
Correspondence Address:
Nazan Cinislioglu
Department of Infections Diseases and Clinical Microbiology, University of Health Sciences Regional Training and Research Hospital, 25040, Palandöken, Erzurum
Turkey
Source of Support: None, Conflict of Interest: None
CheckDOI: 10.4103/0972-9062.337507
Background & objectives: In this study, we aimed to investigate the relationship between serum TGF-β1 and PDGF-B levels with the pathogenesis, clinical course and prognosis of adult Crimean-Congo hemorrhagic fever (CCHF) patients.
Methods: 50 adult patients and 30 healthy individuals as a control group were included in the study, who were followed up and treated with the diagnosis of CCHF at the Atatürk University Faculty of Medicine Infectious Diseases and Clinical Microbiology Clinic, between March 2017 and September 2019 in Eastern Anatolia Region in Turkey. Blood samples were taken from patients on the first day of their hospitalization and on the sixth day of their complaints. TGF-β1 and serum PDGF-B levels were studied by ELISA method using commercial kits, from serum samples taken from CCHF patient group and individuals in healthy control group and stored at -80°C.
Results: While the serum TGF- β1 levels of patients with CCHF were found to be significantly higher on the sixth day of their complaints compared to the first day of hospitalization (42.33 ± 15.42, 28.40 ± 7.06, p = 0.001, respectively), the serum PGDF-B levels were found to be significantly lower on the sixth day of their complaints compared to those measured on the day of hospitalization (62.14 ± 19.75, 93.96 ± 20.02, respectively, p = 0.001).
Interpretation & conclusion: Serum TGF-β1 levels are higher and PDGF-B levels are lower in CCHF patients with severe disease, indicating that serum TGF-β1 and PDGF-B play an important role in the pathogenesis of CCHF.
Keywords: Crimean-Congo hemorrhagic fever; Transforming Growth Factor Beta-1; Platelet Derived Growth Factor Beta
Viral hemorrhagic fever (VHF) is an acute infectious disease which has a high mortality rate and may manifest with fever and hemorrhage. It may render the host’s immune response ineffective through initiating an anti-viral response in the infected host. Although mortality is suggested to result from hemorrhage in VHF, studies have revealed that septic shock and multi-organ failure may also be responsible[1].
The immune response of the host may be negatively affected in patients with Crimean-Congo hemorrhagic fever (CCHF). A poor or absent antibody response, elevated circulating viral load titers and elevated serum cytokine levels indicate that a sufficient antibody response does not develop for controlling the infection[2].
Transforming growth factor-β (TGF-β) is a polypeptide growth factor that plays a role in hemostasis, embryogenesis, immunosuppression, inflammation, proliferation, differentiation, motility, apoptosis, angiogenesis and reconstruction of the micro-environment and the extracellular matrix. It is a miscellaneous agonist that exerts effects according to the response of the target cell. TGF-β is the most potent immunosuppressive growth factor and it suppresses the immune and the inflammatory response through suppressing the effector T (Th1 and Th2) and cytotoxic T cells of the immune system and activating the T-reg cells. TGF-β provides chemotactic stimulants for leukocyte migration. Furthermore, over-production of TGF-β may lead to scar formation and excessive fibrosis[3].
Platelet derived growth factor-B (PDGF-B) is a potent vasoconstrictor growth factor that supports the structural integrity of the vessel wall in addition to many functions under physiological and pathological conditions including embryonic development, tissue homeostasis, wound healing, malignant diseases, atherosclerosis and pulmonary fibrosis. It also has angiogenic effects, affects the endothelial migration and contributes to the integrity of the vascular structures[4].
The immune response, which is effective in controlling the infection and the recovery process, may be impaired in severely ill CCHF patients[1]. The fact that CCHF leads to sepsis, inflammatory cytokines play an important role in the pathogenesis of the disease, and a strong relationship was demonstrated between TGF-β and PDGF-B levels, and sepsis and inflammatory cytokines suggest that TGF-β and PDGF-B levels may be related to the prognosis of CCHF.
In the present study in Eastern Anatolia Region in Turkey, it was aimed to investigate the relationship between the serum TGF-β and PDGF-B levels, and the mortality rates and the clinical course of the disease in CCHF patients who have insufficient or delayed immune response.
Material & MethodsPatient selection
Fifty adult CCHF patients who had been hospitalized at the Infectious Diseases and Clinical Microbiology Clinic of Atatürk University Medical School between March 2017 and September 2019 were included in the study. The control group consisted of 30 healthy volunteers (15 males and 15 females) matched with age and gender, who resided in the same region. No subjects in the study or the control group had a known liver disease, renal or pancreatic insufficiency, acute cardiovascular insufficiency, cerebro-vascular disorder or hyper/hypothyroidism. Subjects who had an acute infection other than CCHF, those who were pregnant, those who had acute or chronic tuberculosis, those with a history of anti-inflammatory drug use within the recent months and whose polymerase chain reaction (PCR) test result was negative for CCHF were excluded.
Study groups
The patients were allocated into two groups as the mild-moderate and the severe disease groups according to the criteria defined by Swanpoel et al. and modified by Ergönül et al., which also include the clinical poor prognosis criteria[5],[6].
Diagnosis of CCHF
Blood samples were obtained from the subjects who voluntarily agreed after the patients or relatives had given their written informed consents. Blood samples were obtained into 5 ml of tubes twice on admission from the patients who were suspected to have CCHF. The blood samples were centrifuged at 4000 rpm after having waited for 30 min and the obtained serum samples were placed into Eppendorf tubes. One of the samples was sent to Erzurum Regional Public Health Laboratory, the reference center of the region, in accordance with the transfer rules established for serological and virological tests used for diagnosing CCHF. The diagnosis of CCHF was made based on the presence of specific anti-IgM antibody detected with immune fluorescence antibody (IFA) and/or PCR test positivity. The patients were those whose CCHF diagnosis had been verified by PCR test positivity.
Assessment of serum TGF-β and PDGF-B levels
TGF-β1 and PDGF-B levels were measured by the ELISA method in the serum samples of patients and controls that had previously been measured and stored at -80°C. While blood samples were obtained from healthy volunteers only once, they were obtained from the patients twice, on the first day of hospitalization and on the sixth day of their complaints. According to the literature data, the deaths of CCHF patients usually occurs after the fifth day of the disease[1]. For this reason, the second serum samples of the patients with a diagnosis of CCHF were collected on the sixth day of the disease when the complaints worsened. The frozen serum samples were placed at -20°C for 48 h before the assessment and at 4°C for 24 h before the assessment. On the day of the study, the samples were kept at room temperature for 30 min and dissolved, and the samples were mixed with vortex. Serum TGF-β1 (SinoGeneClon, Cat No. SG-10060, China) and serum PDGF-B (SinoGeneClon, Cat No. SG-10739, China) were analyzed using the ELISA kits.
Statistical analysis
The Statistical Package for the Social Sciences (SPSS v20) program was used for analysis of the study data. The categorical variables were presented as numbers and percentages, while the numerical variables were presented as mean and standard deviation. The normality distribution of the numerical variables was tested using the Kolmorov Smirnov Test, the z values calculated for skewness and kurtosis were tested using the graphing methods. For comparisons between two independent groups, the T test was used for numerical variables that were normally distributed, the Mann Whitney U test for numerical variables that were not normally distributed, and the Wilcoxon test was used for the comparison of two dependent numerical variables. The χ2 and the Fisher’s exact tests were used for evaluating the distribution of the categorical variables in the groups. The relationships between non-normally distributed continuous variables were investigated using the Spearman’s rho correlation analysis. The ROC (Receiver Operating Characteristic) analysis was performed to determine the usability of the TGF-β1 and PDGF-B variables as diagnostic tests in determining the survival status of the patients. The statistical significance level was accepted as p <0.05 in all analyses.
Ethical statement
The local ethics committee approval was obtained prior to the study (date:22.04.2019/number:3-35).
ResultsFifty patients and 30 healthy volunteers were included in the study. The demographic characteristics of the Crimean-Congo hemorrhagic fever patients and the control group are shown in [Table 1].
Table 1: The demographic characteristics of the Crimean-Congo hemorrhagic fever (CCHF) patients and the control groupThirty-two (64%) patients included in the study had a history of tick contact and 42 (84%) had animal contact. The mean incubation time of patients with a known history of tick contact was found to be 4.98 days. The most common symptoms were loss of appetite (100%), fatigue (96%) and fever (88%). Hemorrhage was observed in 18 out of 50 patients (36%) during their hospitalization or follow-up, and gingival bleeding was the most common form of hemorrhage (20%). Of the patients who had bleeding, 7 (14%) had epistaxis, 2 (4%) had melena, 3 (6%) had vaginal bleeding and 3 (6%) had hematuria. The most common findings on physical examination were found to be oropharyngeal hyperemia (90%), facial hyperemia (84%), rash (76%) and conjunctival hyperemia (74%). Cardiac findings were present in 4 (8%) of the patients. Atrial fibrillation developed in only one (2%) patient and this patient died. When the patients were classified according to their prognosis, 25 out of 50 (50%) were in the severe group and 25 (50%) were in the mild-moderate group. While hemorrhage was observed in 18 of 50 patients (36%), 7 patients (14%) died. While the cause of death was multiorgan failure in 5 out of 7 patients who died, 2 patients died due to chest pain, dyspnea, sudden loss of consciousness and cardiopulmonary arrest. Of the 50 patients, 43 (86%) completely recovered and were discharged.
While the serum TGF-β1 levels of patients with CCHF were found to be significantly higher on the sixth day of their complaints compared to the first day of hospitalization (42.33 ± 15.42, 28.40 ± 7.06, p = 0.001, respectively), the serum PGDF-B levels were found to be significantly lower on the sixth day of their complaints compared to those measured on the day of hospitalization (62.14 ± 19.7593, 93.96 ± 20.02, respectively, p = 0.001). The results of the laboratory parameters measured on the first day of hospitalization and the sixth day of complaints have been displayed comparatively in [Table 2]. These laboratory parameters were used to classify the patients diagnosed with CCHF as mild-moderate or severe alongwith the clinical indicators of poor prognosis.
Table 2: Comparative analysis of the laboratory parameters measured on the first day of hospitalization and on the sixth day of complaints in patients with CCHFWhile there was no significant difference between the patients in the mild-moderate and the severe groups with regard to serum TGF-β1 levels measured on the first day of hospitalization (29.58 ± 8.05, 27.21 ± 5.82, p = 0.449, respectively), the serum TGF-β1 levels measured on the sixth day were found to be significantly higher in the severe group compared to the mild-moderate group (51.22 ± 15.42, 33.45 ± 9.12, respectively, p = 0.001). Furthermore, while no significant difference was observed between the patients in the mild-moderate group and the patients in the severe group with regard to PDGF-B levels measured on the first day of their hospitalization (97.22 ± 22.01, 90.70 ± 17.66, 0.547, respectively), the serum PDGF-B levels measured on the sixth day of hospitalization were found to be significantly lower in the severe disease group compared to the mild-moderate group (56.01 ± 18.11, 68.27 ± 19.75, respectively, p = 0.031). The data obtained according to the prognosis of the disease are shown in [Table 3].
Table 3: Comparative analysis of the laboratory parameters measured on the first day of hospitalization and on the sixth day of complaints in patient groups with mild-moderate and severe diseaseWhen the serum TGF-β1 levels measured on the first day of hospitalization were compared between the patients and the control groups, while no significant difference was determined (28.40±7.06, 25.90±4.28, respectively, p=0.220), the serum TGF-β1 levels measured on the sixth day of complaints were found to be significantly higher compared to the control group (42.33±15.42, 25.90±4.28, respectively p= 0,001,). Furthermore, the serum PDGF-B levels measured on the first day of hospitalization were found to be significantly lower compared to control group (93.96±20.02,119.21±43.38, respectively, p=0.002), and similarly, the serum PDGF-B levels measured on the sixth day of complaints were found to be significantly lower compared to the control group (62.14±19.75, 119.21±43.38, respectively, p=0,001) [Table 4].
Table 4: Comparison of serum TGF-β1 and PDGF-B levels measured on the first day of hospitalization and on the sixth day of complaints between CCHF patients and controlsIn the severe disease group, the dying group and the group with hemorrhage, the serum TGF-β1 levels measured on the sixth day of complaints were determined to be significantly higher than those measured on the day of hospitalization (p=0.001, p=0.018, p=0.001, respectively). Besides, in the severe disease group, the dying group and the group with hemorrhage, the serum PDGF-B levels measured on the sixth day of complaints were determined to be significantly lower than those measured on the day of hospitalization (p=0.001, p=0.028, p=0.001, respectively) [Table 5]. In addition, serum TGF-β1 levels measured on the sixth day of the complaints of the patients in the severe patient group and the dying patient group were found to be significantly higher than the control group (respectively; p= 0.001, p=0.001), serum PDGF-B levels were found to be significantly lower (respectively; p=0.001, p=0.001) [Table 6].
Table 5: Comparison of serum TGF-β1 and PDGF-B levels measured on the first day of hospitalization and on the sixth day of complaints in patients with severe disease, hemorrhage and dying patients
Table 6: Comparison of serum TGF-β1 and PDGF-B levels measured on the sixth day of hospitalization severe disease and dying patients CCHF patients with the control groupNo significant relationship was determined between the serum TGF-β1 levels measured on the day of hospitalization and concurrent non-specific laboratory parameters (WBC, AST, ALT, CPK, LDH, creatinine, INR) (p>0.05). The laboratory parameters measured on the sixth day of complaints (WBC, AST, ALT, CPK, LDH, creatinine, INR) and the serum TGF-β1 levels were compared and while a significant, positive and weak correlation was detected between the serum TGF-β1 levels and AST, ALT, LDH and INR, no significant correlation was determined between the WBC, CPK, creatinine and serum TGF-β1 levels (p=0.675).
ROC analysis was performed in order to determine whether the TGF-β1 and PDGF-B variables could be used as a diagnostic test for determining a poor prognosis. The area under the curve (AUC=0.818) estimated for the sixth day TGF-β1 was sufficient for use for diagnostic purposes (AUC>0.5) [Figure 1]. It was seen that the test had a predictive value for estimation of the clinical course of the disease by taking 45, 62 as the cutoff value, as AUC was quite good in the ROC analysis for the TGF-β1 variable; the test sensitivity was 72% and the specificity was 96%.
Figure 1: ROC curve analysis of TGF-β1 and PDGF-B for determining a poor prognosis in CCHF patients. TGFB1_1: Transforming growth factor beta-1 level measured on the first day of hospitalization, TGFB1_6: Transforming growth factor beta- 1 level measured on the 6th day of the patients’ complaints, PDGFB_1: Platelet Derived Growth Factor-B level measured on the first day of the patients’ complaints, PDGFB_6: Platelet Derived Growth Factor-B level measured on the 6th day of the patients’ complaints.ROC analysis was performed in order to determine whether the TGF-β1 and PDGF-B variables could be used for determining the mortality. The area under the curve (AUC=0.890) estimated for the sixth day TGF-β1 was sufficient for use for diagnostic purposes (AUC>0.5) [Figure 2]. It was seen that the test had a predictive value for estimation of the mortality rate of the disease by taking the cutoff value as 55, 09, as AUC was quite good in ROC analysis for the TGF-β1 variable measured on the sixth day of complaints; the test sensitivity was 100% and the specificity was 86%.
Figure 2: ROC curve analysis of TGF-β1 and PDGF-B for determining the mortality in CCHF patients. TGFB1_1: Transforming growth factor beta-1 level measured on the first day of hospitalization, TGFB1_6: Transforming growth factor beta- 1 level measured on the 6th day of the patients’ complaints, PDGFB_1: Platelet Derived Growth Factor-B level measured on the first day of the patients’ complaints, PDGFB_6: Platelet Derived Growth Factor-B level measured on the 6th day of the patients’ complaints. Discussion Although the number of studies on Crimean-Congo hemorrhagic fever (CCHF) disease are increasing day by day, there are still many unanswered questions. Despite various studies that have been conducted to elucidate the pathogenesis of this disease, which is characterized by systemic involvement and may result in death, the pathogenesis of the disease is still not fully elucidated[1].
There are data available which indicate that a sufficient immune response is not formed in cases that result in mortality in CCHF. As with all infections, the immune response is important in limiting the infection and in the healing process[7]. The immune response is impaired in severe CCHF patients. CCHF disease leads to sepsis and inflammatory cytokines that plays an important role in the pathogenesis of the disease. In this study, which we started with the hypothesis that TGF-β1 and PDGF-B levels, which are known to be strongly associated with sepsis and inflammatory cytokines, may play a role in the prognosis of CCHF, the high serum TGF-β1 levels and the low serum PDGF-B levels were found to be significantly associated with the clinical course and mortality of the disease.
In a retrospective study conducted by Yilmaz et al. in 2017 on the prognostic significance of the TGF-β1 level in CCHF patients, the serum TGF1 level was measured once in the patient group and compared with the control group[8]. The serum TGF-β1 level was found to be lower in the CCHF patient group compared to the control group. In addition, in this study, the low level of serum TGF-β1 in CCHF patients with poor prognosis was associated with the low level of platelets from which TGF-β1 is secreted. In the present study, unlike previous studies conducted to determine the prognosis of CCHF disease, we studied the serum levels twice, both on the first day of hospitalization and on the sixth day of their complaints and compared these data with each other instead of a single blood sample from patients. On the contrary to the study of Yilmaz et al., in the present study, while no significant statistical difference was determined between the serum TGF-β1 levels measured on the first day of hospitalization and the values of the control group, the serum TGF-β1 levels measured on the sixth day of complaints were determined to be significantly higher compared to those measured in the control group[8]. Furthermore, it was determined that the serum TGF-β1 levels measured on the sixth day of complaints were found to be higher compared to the values measured on the first day of hospitalization; the serum TGF-β1 levels were higher in the severe disease group compared to the mild-moderate group and higher in dying patients compare to those who survived.
TGF-β1 is not only derived from platelets; it is also an important member of macrophage-derived cytokines[3]. Cytopenia in CCHF patients has been suggested to result from hemophagocytic syndrome[9]. Hemophagocytic syndrome is associated with Th-1 cell-derived cytokines including TNF- α, IL-6, IL-1, activated macrophages and IFN-γ[10]. Histopathological findings consistent with hemophagocytic syndrome (destruction of erythrocytes, leukocytes and platelets by reactive histiocytes) were encountered in bone marrow biopsies of CCHF patients[11]. Pancytopenia and thus thrombocytopenia that can develop during the disease may be due to the high levels of activated macrophages[1]. This suggests that the increase in serum TGF-β1 levels in the progressive stages of the disease is due to increased macrophage activity, which has an important role in the pathophysiology of CCHF disease. In addition, we suggest that measuring the TGF-β1 level in the same patient at different times in our study and designing it prospectively made our statistical results more significant. Our study can be regarded as the first study in the literature that prospectively investigates the relationship between the prognosis of the disease and the TGF-β1 levels measured at two different times in the same patient with CCHF.
The common properties of angiogenesis include abnormal vascular permeability and defective vascular reformation and maturation that promote leakage, bleeding and inflammation[12]. The influences of TGF-β1 on angiogenesis were investigated by Stiles et al. and Muppala et al. and both studies determined that TGF-β1 increased angiogenesis[13],[14]. In the present study, when the patients with or without hemorrhage were compared with regard to the TGF-β1 levels measured on the sixth day of their complaints, the TGF-β1 levels were found to be statistically significantly higher among patients with hemorrhage. We consider that the angiogenic effect of TGF-β1, which may increase hemorrhage, may play a role in the pathogenesis and prognosis of the disease.
TGF-β1 is among the most potent immunosuppressive molecules. TGF-β1 suppresses the immune and inflammatory response through suppressing the T helper /Th1 and Th2) and cytotoxic T cells and activating the T-reg cells[15]. The excessive inflammatory response that develops in sepsis is attempted to be balanced with contracting molecules, mediators and cytokines. The reduction in the T-cell response and anergy observed in a significant portion of sepsis patients is an excessive contra-response toward balancing the pro-inflammatory response that emerges initially. This condition may also lead to future organ failure[16]. Gupta et al. reported that elevated anti-inflammatory cytokine levels in the sera of 131 Ebolavirus-infected patients of whom 44 died, were correlated with a fatal course[17]. Hutchinson et al. reported in their study conducted with 87 Sudan Ebolavirus-infected patients of which 34 died, that anti-inflammatory and immunosuppressive cytokines were significantly higher in the patients with occurring death[18]. In the study by Saksida et al. conducted with CCHF patients, the anti-inflammatory cytokine levels were reported to be elevated[19]. Under the light of these studies, excessive inflammatory response may be stated to be responsible for the poor prognosis in CCHF patients. Elevated serum levels of TGF-β1 a potent anti-inflammatory, suggests that it is a part of the immune response against CCHF infection in patients who have severe inflammation, severe disease, hemorrhage or those who die.
Many clinical studies have shown that high blood or urine TGF-β1 levels in cancer patients is an important parameter in predicting the prognosis of the disease[20]. The TGF-β1 levels were shown to increase in patients with pancreatic carcinoma compared to the control group in the study by Karabulut et al., and Gupta et al. showed that elevated TGF-β1 levels can induce the motility and invasion of bladder cancer cells[21],[22]. Furthermore, although TGF-β1 is required for wound healing; excessive production of TGF-β1 can cause excessive accumulation of scar tissue and fibrosis[23]. Many studies have shown that increased TGF-β1 levels cause fibrosis in organs, especially in the liver and the kidneys[24],[25]. In our study, we found that there was no significant relationship between the TGF-β1 level, and AST and ALT levels studied simultaneously, while the serum TGF-β1 levels measured on the sixth day of the patients› complaints, and AST and ALT values, which are the indicators of liver damage in CCHF patients, were found to be significantly correlated. The results of previous studies and the present study suggest that elevated serum TGF-β1 levels in CCHF patients with poor prognosis can contribute to liver damage, kidney damage and multiorgan failure by increasing organ fibrosis.
PDGF-B is a growth factor that supports the structural integrity of the vascular wall, which has many important functions under physiological and pathophysiological conditions such as embryonic development, tissue homeostasis, wound healing, malignant diseases, atherosclerosis and lung fibrosis. Platelets are stimulated and secrete the substances in their granules in the thrombus formation process. PDGF-B plays an important role in the healing of the injured vessel wall[4]. In the study of Brueckman et al. investigating the prognostic value of PDGF-B in sepsis patients, the likelihood of sepsis-related deaths is 7.3-fold greater in patients with low PDGF-B levels compared to patients with high PDGF-B levels[26]. In the study of Berk et al., PDGF-B was reported to act as a potent vasoconstrictor and contributed to the integrity of the vascular structure[27]. Heldin and Westermark reported that PDGF-B had important roles in the wound healing process[28]. In the present study, PDGF-B levels measured on the first day of hospitalization and on the sixth day of complaints were found to be statistically significantly lower compared to the control group. While the serum PDGF-B levels measured on the first day of hospitalization did not differ between the dying and surviving patients and between those with or without hemorrhage, the PDGF-B levels measured on the sixth day of complaints were found to be statistically significantly lower in patients with severe disease compared to those with mild-moderate disease, and in dying patients than the surviving patients. In the light of the studies conducted to elucidate the patho-physiogenesis of PDGF-B, the lower serum PDGF-B levels in patients who died and in the severely ill group can be accepted as an expected result[29],[30]. In addition, the low serum levels of PDGF-B in the dying and in the severely ill patients may be due to the destruction and loss of function of endothelial cells and platelets from which PDGF-B is synthesized in CCHF disease.
In our study, the elevated serum TGF-β1 levels in CCHF patients compared to healthy individuals, higher serum TGF-β1 levels in patients with poor prognosis, hemorrhage and dying patients, lower PDGF-B levels in patients with poor prognosis and dying patients reveal that TGF-β1 and PDGF-B have important roles in CCHF pathogenesis. These results suggest that both parameters may guide clinicians about the clinical course and mortality in CCHF patients.
ConclusionWe suggest that the serum TGF-β1 and PDGF-B levels have important role in CCHF pathogenesis; these may function as useful laboratory parameters for risk classification. The determination of the serum TGF-β1 and PDGF-B levels in CCHF patients can guide clinicians as markers in predicting the disease prognosis. We consider that studies with larger series in which the viral load and other immunological system elements are evaluated together are needed in order to reach definitive conclusions on this subject.
Conflict of interest: None
References
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