The Possible Role of HHV-6, HHV-7 and EBV in Patient with Bell's Palsy
Raheif et al (2021): The possible role of HHV-6, HHV-7, and EBV © Annals of Tropical Medicine & Public Health DOI: http://doi.org/10.36295/ASRO.2021.24532
The possible Role of HHV-6, HHV-7 and EBV in Patient with Bell's palsy
Rafal Hashim Raheif1, Asmaa B. Al-obaidi1,Abdul-Kareem K Al-Khazrajee2, Haidar A. Shamran 3
1Microbiology Department/ School of Medicine, Al-Nahrain University, Baghdad, Iraq 2Surgery Department, School of Medicine, Al-Nahrain University, Baghdad, Iraq 3Medical research Unit, School of Medicine, Al-Nahrain University, Baghdad, Iraq Corresponding author: Haidar A. Shamran, [email protected]
Abstract Introduction: Bell’s palsy (BP) is an acute, generally unilateral, paralysis or weakness of facial musculature consistent with peripheral facial nerve dysfunction, different factors suspected to be contributed to the development of BP including herpes viruses. The objective of this study is to detect human herpes viruses 6 and 7 (HHV-6, -7) and Epstein-Barr virus (EBV) in the saliva samples of patients in the early presentation of BP. Patients and Methods: A case-control study included saliva samples taken from 50 patients with BP and 50 apparently healthy controls without any neurological deficit, viral DNA was extracted from the saliva and then subjected for quantitative real time-PCR for detection of HHV-6 and -7 and EBV viral load (VL) in saliva. Results: HHV-6 DNA was positive in 22 (44%) out of the 50 patients, and in 12 (24%) of the controls (p=0.028), with a significantly higher mean viral load (p=0.002), in addition, 70% of HHV-6 positive patients had severe grades with a significantly higher VL (p=0.007) and (0.015) respectively. While HHV-7 was significantly higher in the controls (p=0.046), in 37 (74%) of the controls versus 28 (56%) of the patients, however HHV-7 was higher in the first day of presentation in BP patients (p=0.007). Regarding EBV DNA 36% (18 out of the 50) patients, and 8% of the controls had positive EBV in saliva (p=0.001), with also significantly higher mean viral load was in patients (p=<0.001). Twenty percent of patients (10/50) had triple viral infections and seven out of these ten had severe grades of BP. Conclusion: HHV-6 and EBV could play an important role in the development of BP and HHV-6 might have a neuro-pathological effect in severe cases of BP, however HHV-7 doesn't seem to play a role in the pathogenesis of the disease.
Key words: HHV-6, HHV-7, EBV, Bell's palsy, Saliva
DOI: http://doi.org/10.36295/ASRO.2021.24532 Page: 407-414
Volume/Issue: Volume: 24 Issue: 05
List of Abbreviations HHV-6: Human Herpes Virus 6 HHV-7: Human Herpes Virus 7 EBV: Epstein Barr Virus Bp: Bell's palsy VL: Viral Load
Introduction Bell’s palsy (BP) is the most common condition involving a rapid and unilateral onset of peripheral paresis/paralysis of the seventh cranial nerve. It affects 11.5–53.3 per 100,000 individuals a year across different populations. Bell’s palsy is a health issue causing concern and has an extremely negative effect on both patients and their families. Therefore, diagnosis and prompt cause determination are essential for early treatment. (1)
Despite its severe effects, the exact etiology of BP remains unclear. The Guideline Development Group (GDG) (2) has identified the diagnosis of BP as one of exclusion, requiring careful clinical elimination of other potential etiologies of facial paralysis/paresis, such as trauma, neoplasms, postsurgical facial paralysis/paresis, or infection by agents including herpes viruses and Lyme disease. (1,3). Some studies stressed on the role of HHV-6 and HHV-7 in the development of Bell's palsy (4, 5), Human herpes virus 6 and 7 (HHV-6 and HHV-7; family Herpes viridae, subfamily Beta herpes virinae, genus Roseolo virus, species Human herpes virus 6 and 7) are neurotropic viruses that reactivate frequently in immune compromised persons (6,7).
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Several studies had been conducted on the possible role of HHV-6 in the etiology of Bell's palsy, it is suggested that the high level of HHV-6 DNA is only a consequence of the patient’s immune status, this may be the main predisposing factor for the occurrence of the palsy although the contribution of HHV-6 reactivation/replication cannot be ruled out (4, 8, 9).
HHV-7 is highly prevalent with 75–90 % of healthy adults harboring the virus (10, 11). Infectious HHV-7 is frequently present in the saliva of healthy humans and it is a highly neurotropic virus and could be implicated in the pathology of Bell's palsy (11, 5). Epstein-Barr virus (EBV) is a double-stranded DNA virus belonging to the Herpes family. EBV is found in saliva and is therefore transmitted through coughing, the sharing of food, kissing (hence the layman’s term ‘kissing decease’), etc. Low amounts of EBV may be detected in saliva throughout life in infected individuals (12-13).Several study stressed on the role of EBV in many neurological complications including Bell's palsy (14-15).
Patients and Methods A case-control study was conducted from October 2019 to February 2020. Fifty patients with idiopathic unilateral facial nerve paralysis (Bell's Palsy) were collected from Al-Imamain Al-Kadhimain Medical City and Baghdad teaching hospital. And 50 apparently-healthy age- and sex-matched volunteers as controls. A written informed consent was taken from each subject enrolled in this study. The study was approved by the Institutional review board (IRB) of the College of Medicine-Al-Nahrain University, approval number (269-15-10-2019). The research was conducted in the microbiology department at the College of Medicine-Al-Nahrain University.
From all patients and controls about 1-2ml saliva (without induction) were collected in plane tubes. Saliva samples preserved in deep freeze (-20 ºC), and then used for viral DNA extraction. Viral nucleic acid was extracted using (Geneaid/Taiwan) kit. Sacace (Italy) real time amplification kit was used for quantitative detection of HHV-6,HHV-7and EBV in the saliva samples. 15 µl of master mix was added to all PCR tubes and 10 µl of (DNA sample, negative control, positive control or standards) were added to master mix. Real time PCR instrument used in this work was STRATAGENE MX 3005P (Agilent Technologies, USA). For real-time PCR the following amplification protocol was used: 1 cycle at 95°C for 15 min followed by 5 cycles consisting of 5 s at 95 °C, 20 s at 60 °C, and 15 s at 72 °C, and then 40 cycles consisting of 5 s at 95 °C, 30 s at 60 °C, and 15 s at 72 °C.
Statistical Analysis The Statistical Package for Social Sciences (SPSS Inc., Chicago,IL, USA), Version 20 used for statistical analysis. Categorical data formulatedas count and percentage. Chi-square test used to describe the association ofthese data. Alternatively, Fisher exact test was used if there is 25% of cells lessthan expected count. Numerical data were described as mean and standarddeviation. Independent sample t-test used for comparison between two groups.The lower level of accepted statistical significant difference isequal or less than 0.05.
Results In this study HHV-6, HHV-7 and EBV viral loads (VL) were measured in the saliva samples of Bell's Palsy patients and normal controls by quantitative real time PCR. HHV-6 DNA was positive in 22 (44%) out of the 50 patients, and in 12 (24%) of the controls (p=0.028), and the mean viral load was also significantly higher in patients than in the controls (p=0.002), tables (1) and (42).
Table (1): Comparison of the number of HHV-6 DNA positive cases between patients and controls
Patients Controls
Positive 22 12 % 44.0% 24.0% HHV-6 Negative 28 38 % 56.0% 76.0%
Total 50 50
% 100.0% 100.0% p value 0.028* Odds Ratio 2.488 (1.06-5.85)
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Table (2): Comparison of the mean VL of HHV-6 between patients and controls
Study groups HHV-6 Patients Control Mean 4026.00 117.04 Standard Deviation 9912.57 252.71 Median 0.00 0.00 Percentile 25 0.00 0.00 Percentile 75 3000.00 0.00 P value 0.002*
Table (3) demonstrated no significant association between HHV-6 positivity with patients' age, sex, side of the weakness or duration of BP, however there was a significant association between HHV-6 and the severity of BP, in which 70% of HHV-6 positive cases were in the severe grades (p=0.007), also the mean HHV-6 VL is significantly higher in the severe grades (p=0.015).
Table (3): The associations between HHV-6 DNA positivity and viral load with patients' clinical and demographic data
HHV6 P value Mean VL Standard Deviation P value Positive Negative <=25 years 9 (45.0) 11 (55) 6640.00 14686.42 Age groups 0.907 0.125 >25 years 13 (43.3) 17 (56.7) 2283.33 4105.51 Female 8 (66.7) 4 (33.3) 6608.33 13971.04 Sex 0.073 0.305 Male 14 (36.8) 24 (63.2) 3210.53 8321.77 Left 9 (39.1) 14 (60.9) 2265.22 4514.58 Side 0.577 0.250 Right 13 (48.1) 14 (51.9) 5525.93 12761.50 Moderate 10 (30.3) 23 (69.7) 630.30 1072.52 Severity 0.007 0.015 Severe 12 (70.6) 5 (29.4) 10617.65 15121.85 1 4 (40) 6 (60) 1000.00 1333.33 Duration 2 3 (30) 7 (70) 0.522 1330.00 2921.21 0.253 days 3 15 (50) 15 (50) 5933.33 12385.35
On the other hand, HHV-7 DNA was positive in the saliva of(56%) 28 out of the 50 patients versus 37 (74%) of the controls, which is significantly higher in the controls (p=0.046), however the mean viral load was higher in patients than in the controls, tables (4) and (5).
Table (4): Comparison of the number of HHV-7 DNA positive cases between patients and controls
Patients Control
Positive 28 37 % 56.0% 74.0% HHV-7 Negative 22 13 % 44.0% 26.0% Total 50 50 % 100.0% 100.0% p value 0.046* Odds Ratio 0.447 (0.192-1.09)
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Table (5): Comparison of the mean VL of HHV-7 between patients and controls
Study groups HHV-7 Patients Controls Mean 12440.00 2245.20 Standard Deviation 26839.02 2788.47 Median 3000.00 825.00 Percentile 25 0.00 0.00 Percentile 75 10000.00 5000.00 P value 0.397 NS
Table (6) demonstrated no significant association between HHV-7 positivity with patients' age, sex, side of the weakness or severity of BP, however HHV-7 was significantly higher in the first day of BP presentation (p=0.007).
Table (6): The associations between HHV-7 DNA positivity and viral load with patients' clinical and demographic data.#
HHV7 P value P value Mean VL Standard Deviation Positive Negative <=25 years 13 (65) 7 (35) 11300.00 22162.32 Age groups 0.295 0.809 >25 years 15 (50) 15 (50) 13200.00 29896.83 Female 7 (58.3) 5 (41.7) 13500.00 28163.48 Sex 0.852 0.877 Male 21 (55.3) 17 (44.7) 12105.26 26789.26 Left 10 (43.5) 13 (56.5) 12347.83 28439.10 Side 0.100 0.982 Right 18 (66.7) 9 (33.3) 12518.52 25945.76 Moderate 19 (57.6) 14 (42.4) 16303.03 32133.01 Severity 0.754 0.048 Severe 9 (52.9) 8 (47.1) 4941.18 7101.68 1 10 (100) 0 (0) 16300.00 29803.24 Duration 2 4 (40) 6 (60) 0.007 13400.00 31127.69 0.854 Days 3 14 (46.7) 16 (53.3) 10833.33 25152.07
In addition, EBV DNA was positive in the saliva of (36%) 18 out of the 50 patients, and in only (8%) 4 out of the 50 controls (p=0.001), and the mean viral load was also significantly higher in patients than in the controls (p=<0.001), tables (7) and (8). It worth to mention that ten patients had triple viral infections among a total of 37 positive cases (by including any of the three viruses studied), i.e. 20% of patients and none of the controls. Seven out of these ten patients with triple viral infection (70%) had severe grades of BP.
Table (7): Comparison of the number of EBV DNA positive cases between patients and controls
Study groups
Patients Patients Positive 18 4 % 36.0% 8.0% EBV Negative 32 46 % 64.0% 92.0% Total 50 50 % 100.0% 100.0% p value 0.001** Odds Ratio 6.469 (2-20.19)
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Table (8): Comparison of the mean VL of EBV between patients and controls
Study groups EBV Patients Patients Mean 414155.60 306.00 Standard Deviation 1530432.82 1071.03 Median 0.00 0.00 Percentile 25 0.00 0.00 Percentile 75 71000.00 0.00 P value <0.001**
Table (9): The associations between EBV DNA positivity and viral load with patients' clinical and demographic data
EBV Standard P value Mean VL P value Positive Negative Deviation <=25 years 8 (40) 12 (60) 382739.00 1559975.42 Age groups 0.630 0.907 >25 years 10 (33.3) 20 (66.7) 435100.00 1536893.00 Female 5 (41.7) 7 (58.3) 49666.67 104898.29 Sex 0.639 0.349 Male 13 (34.2) 25 (65.8) 529257.37 1744104.35 Left 8 (34.8) 15 (65.2) 643251.30 2007376.61 Side 0.868 0.334 Right 10 (37) 17 (63) 219000.00 958428.23 Moderate 12 (36.4) 21 (63.3) 456387.27 1689545.92 Severity 0.941 0.789 Severe 6 (35.3) 11 (64.7) 332176.47 1205451.33 1 6 (60) 4 (40) 49528.00 76427.42 Duration 2 3 (30) 7 (70) 0.210 49528.00 2950177.78 0.043 days 3 9 (30) 21 (70) 206266.67 909550.28
Finally, table (9) demonstrated no significant association between EBV positivity with patients' age, sex, side of the weakness or severity of BP, however EBV VL was significantly higher in the third day of BP presentation (p=0.043).
Discussion To our knowledge, this is the first study that made an in-depth analysis of HHV-6, HHV-7 and EBV in saliva samples from Bell’s palsy patients. Others have investigated the role of HHV-6 alone herpesvirus in the etiology of BP(16).Human herpes virus 6 is a common neurotropic virus which has been associated with conditions such as febrile convulsions, encephalitis, and multiple sclerosis and is another candidate in Bell’s palsy(8). HHV-6 has been directly or indirectly associated with several neurological diseases (17, 18), in cases of primary infection in immune-competent young children, reactivation in healthy adults (19), or in immunosuppressed patients (20).
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The present study found that both the number of HHV-6 positivity and its mean VL in saliva were significantly higher in patients than in the controls, which is supported by the study of Turriziani et al in (2014) (4) which showed that the value of HHV-6 DNA copies was significantly higher than that detected in healthy subjects. In addition, patients with the highest levels of HHV-6 DNA showed no change in facial palsy HB grade or even an increase of at least one HB grade at the first visit. This suggests that the high level of HHV-6 DNA is only a consequence of the patient’s immune status: this may be the main predisposing factor for the occurrence of the palsy although the contribution of HHV-6 reactivation /replication cannot be ruled out. These finding also agrees with results of the current study in which 70% of HHV-6 positive cases were in the severe grades (p=0.007), also the mean HHV-6 VL is significantly higher in the severe grades (p=0.015).
One study searched for HHV-6 in the tear fluid of patients with BP, finding a significantly higher detection rate of HHV-6 than that in healthy controls (8). In addition, recently a study of HHV-6 in saliva of children and adolescents with BP found even a higher frequency of HHV-6 in patients than the current result (21). However it is still uncertain whether HHV-6 is involved in the development of the disease or that the underlying disease mechanism might predispose patients to HHV-6 reactivation. Perhaps the major limitations of this study are that the species of HHV-6 detected in samples were not characterized, and absence of follow up VL levels in these patients. Due to the close association between HHV-6 and HHV-7 (22, 23), HHV-6 and HHV-7 DNA have been detected in CSF and other body fluids by polymerase chain reaction (PCR), which implicates a role of these viruses in neurologic disorders (6). HHV-7 is a virus that is highly prevalent and has been detected in normal brain tissues (10). However in contrast to HHV-6, HHV-7 was significantly higher in healthy controls as compared to BP patients. These findings are supported by several studies that isolated HHV-7 at high frequency in the saliva of healthy subjects (24-25). In particular, little is known about the pathogenic role of HHV-7 in central nervous system (CNS) disease in non-immunosuppressed adults (10, 22). Also there are conflicting results about the association of HHV-7 with BP or with some other neurological diseases (11, 26). In addition, Kanerva et al in 2009 (5) found an equal presence of HHV-7 in both BP patients and controls.
Primary HHV-7 infection usually occurs during childhood and causes several clinical manifestations: mainly exanthemsubitum (roseolainfantum), followed by a lifelong latent state with possible reactivation in case of immunodeficiency. Nevertheless, some considerably different approaches exist regarding the natural history of HHV-7 and the possible consequences of HHV-7 infection in immune-competent adults (10). In the current study, HHV-7 was higher in the saliva of BP patients than in controls (which is opposite to that of HHV-6), though the frequency of HHV-7 was significantly higher in healthy controls, these findings can be explained by the study of Ward et al in 2005, (22) which demonstrated that for HHV-7 the absence of previous HHV-6 infection may predispose to neurological morbidity, perhaps because previous HHV-6 infection affords some protection due to limited immunological cross reactivity between the viruses. So that the opposite could be true in the saliva, in which HHV-7 VL could be high in BP patients as a protective role against HHV-6. This also might explain the higher frequency and VL of HHV-7 in the first day of BP presentation than in the second and third days (table 6), which could be regarded an early protective role of HHV-7 against HHV-6.
On the other hand, the sero-prevalence rate of EBV in this country can be considered high reaching up to 80% (27). In addition EBV was detected in high levels in the saliva in several researches (12-13). This study found that both the frequency and VL in of EBV is significantly higher in BP patients than in the controls, this finding is supported by several researches and case reports on the possible role of EBV in the pathogenesis of BP (14, 28, and 31). The study of Wochenschr and Matos in 2017 (32) reported high frequency of EBV infection in pediatrics with otitis media which caused BP. However the current study found no significant association between EBV infection and young age group, this could be explained by relatively lower seroprevalence rate of EBV in young Iraqi subjects (27), so that the virus had more opportunity to infect adults just like pediatrics.
Also seronegative patients are more susceptible to increasing EBV VL and more severe clinical signs and symptoms of facial nerve paralysis (28, 15). Which is seen the results of this study in which EBV VL was significantly higher in the third day of presentation (table (4-12)), that means an increasing in the viral load is associated with the disease progression over time. Neurological complications, such as cranial nerve palsies, Guillain-Barrè syndrome, meningoencephalitis, and mononeuritis multiplex, occur in 1 to 5% of all patients with acute EBV infection (4). Neurological manifestations may be the only clinical signs, particularly in children, leading to a delay in diagnosis. Several cases of facial nerve paralysis associated with EBV infection are reported (33).
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The pathogenesis of EBV-associated neurological complications is not well-known. There are several unconfirmed possibilities. First, it is possible that EBV directly affects neurons and/or the endothelium. Lytic replication of EBV in the brain is confirmed by detection of its messenger RNA in the CSF taken from patients with encephalitis or central nervous system lymphoma. A second possibility is that EBV-infected B cells in an activated state release several pro-inflammatory cytokines, which in turn cause injury to the surrounding parenchyma. The third possibility is that EBV-infected B cells are actively attacked by EBV-specific cytotoxic T-lymphocytes resulting in injury to the surrounding parenchyma in the brain(34, 15).
Although the role of HHV-6, EBV and even HHV-7 in the pathogenesis of BP have not been confirmed yet. Findings of the present study suggest a possible synergistic effect among these viruses, because (10/50) 20% of patients and none of the controls had triple viral infections among a total of 37 positive cases. Seven out of these ten patients with triple viral infection (70%) had severe grades of BP. Turriziani et al in 2014 (4) suggested that co-infection with this HHV-6 is possible, and could be more implicated in the pathogenesis of BP. The combined role of viruses also could be explained by the autoimmune theoryin which viral replication may provoke an autoimmune reaction against peripheral nerve myelin components, leading to the demyelination of cranial nerves, especially the facial nerve (35). This is supported by studies on multiple sclerosis which could be caused by autoimmune reaction to multiple herpesviruses interactions especially antibodies against HHV-6, HHV-7 and EBV that cross react with myeline basic protein (36).
Recently Ptaszynska-Sarosiek et al in 2019 (9) have revealed a common presence of the herpesviruses (including HHV-6 and EBV) in trigeminal and facial nerve ganglia post-mortem among a random group of Polish population and demonstrated simultaneous infection of the ganglia with different herpesviruses. Which support the results of the present study that detected a combined infection by three herpesviruses.Conclusions,the significantly high frequency and viral load of HHV-6 and EBV in Bell's palsy make them possible players in the pathogenesis of this disease. The high HHV-6-frequency and viral load in severe HB grades of BP strengthens its role in this neurological condition. Human herpes virus-7 might not have a role in the pathogenesis of facial nerve paralysis.
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