Review Article
PREVALENCE OF EQUINE HERPESVIRUSES (EHVS) INFECTION IN EGYPT: SYSTEMATIC META-ANALYSIS
M. Marzok1, A. Al-mubarak2, M. Elgioushy3 and S. El-khodery4
1Department of Clinical Sciences, College of Veterinary Medicine, King Faisal University, Al-Ahsa, Saudi Arabia
2Department of Microbiology, College of Veterinary Medicine, King Faisal University, Al-Ahsa, Saudi Arabia
3Department of Animal Medicine, Faculty of Veterinary Medicine, Aswan University, Aswan 37916, Egypt.
4Department of Internal Medicine, Infectious Diseases and Fish Diseases, Faculty of Veterinary Medicine, Mansoura University, Manosura 35516, Egypt
Corresponding author’s email: mmarzok@kfu.edu.sa ; marzok2000@hotmail.com
ABSTRACT
This report aimed to perform a meta-analysis on the occurrence of Equine herpesvirus (EHV) infection in Egypt. This systematic meta-analysis was performed in accordance with the PRISMA guidelines. Data were retrieved after a complete search, and eligible articles were identified. Data analysis with random-effects model was performed using a comprehensive meta-analysis software program. The results were presented as effect size, confidence intervals (CI), heterogeneity, and publication bias. A total of 1760 horses from 20 accepted studies were investigated for EHVs infection. Of these, 740 horses were found positive for EHVs, with a prevalence of 42%. The highest prevalence (100%) was during 2016 and 2020. EHV-1 was the most prevalent strain affecting horses in Egypt (p < 0.05). The prevalence of isolated strains was as follows: EHV-1 (492, 66.48 %), EHV-2 (151, 20.40 %), EHV-4 (105, 14.19 %), and EHV-5 (88, 11.89 %). The mixed EHV-1 and EHV-4 infections were predominant. However, the EHV-3 was not detected in any of these studies. At random effects, the Z-value was -1.539 (p-value = 0.124). The Q-value (373.103), I-squared (95.17), and p-value (0.000) were the final heterogeneity variables. The Egger’s linear regression test did not imply a publication bias, and its outcomes were intercept (-3.66), and 95% confidence interval (-8.23 to -0.9). The results of the present meta-analysis indicated a high prevalence of EHV infection in Egypt, particularly EHV-1. Therefore, more attention should be paid to the prevention and control of this disease.
Keywords: Horse, Epidemiology, EHV, Systematic review
INTRODUCTION
Equine herpesviruses (EHVs) are infectious agents that have deleterious effects on equine health (Lunn et al. 2009). They are large, enveloped, linear, double-stranded DNA viruses of the Herpesviridae family (Gatherer et al. 2021). Nine strains of herpesvirus have been recorded (Davison et al. 2009). EHV-1 and EHV-4 are considered the most important herpesviruses because of their high prevalence, ability to reactivate latent infections, and different clinical presentations (Pavulraj et al. 2021).
Clinical signs in infected animals vary depending on the type of EHV involved. Both EHV-1 and EHV-4 can cause severe respiratory syndromes. Horses infected with EHV-1 can show abortions in pregnant mares, neurological manifestations with high mortality rates in foals (Pavulraj et al. 2021; Slater et al. 2006). In addition to lymphadenopathy in foals, the most common clinical signs of EHV-2 in foals and adult horses include upper respiratory tract symptoms and keratoconjunctivitis (Borchers et al. 2006). The EHV-3 causes equine coital exanthema, an acute venereal mucocutaneous disease in mares and stallions (Vissani et al., 2021).
Equines can acquire EHV horizontally through direct contact with the nasal discharge of infected animals or EHV-1-positive aborted fetuses or indirectly through contact with contaminated fomites (Allen et al. 2004). Vertical transplacental transmission from infected mares to their offspring or through the venereal route via semen from an infected stallion has been identified as a method of transmission of EHV-3 (Negussie et al. 2016). The herpesviruses often remain latent in the host brain and lymphoid tissues after infection with no lytic viral replication (White et al. 2012). The compromised immune system of the host may cause the virus to reactivate, leading to viremia and shedding of the virus into the environment (Reese, 2016).
The clinical manifestations of EHV infections are not reliable tools for accurate diagnosis as they may mimic those of other infectious diseases. Therefore, EHVs are diagnosed using several laboratory serological tests for antibody detection, including enzyme-linked immunosorbent assay (ELISA), viral neutralization, and complement fixation (Bannai et al. 2013; Lang et al. 2013). Viral isolation is considered the standard diagnostic procedure for EHVs (Hartley et al. 2005). Recently, several molecular techniques have been used to detect the genomic materials of EHVs, including polymerase chain reaction (PCR) (Pusterla et al. 2009) and real-time PCR, which are considered the most sensitive molecular techniques for EHV detection (Smith et al. 2012).
The study population and presence of risk factors are determinants of the prevalence of infectious diseases (Buitrago-Garcia et al. 2022). Variables such as age and sex of the horses studied have been linked to a higher risk of EHV infection. Young foals are more likely to be infected with EHV-2/-5 than adult horses (Hue et al. 2014) while equids aged 3–8 years have a higher prevalence of EHV-1/-4 than those younger than 3 years (Worku et al. 2024). The gender differences have also been observed, with males being more likely to contract EHV-1 and-2 (Bolfa et al. 2017). However, several studies have recorded higher infection rate of EHV-1 and -4 among females than among males (de Souza et al. 2017; Negussie et al. 2016).
In Egypt, many epidemiological studies have investigated the prevalence of EHVs in horses, showing clinical signs indicative of EHV infection. The prevalence of EHV infection varies spatially and temporal variation (A Salib et al. 2016; Ata et al. 2020; Abdel-Rady et al. 2022; Ahdy et al. 2022; Khattab et al. 2022). Moreover, there was variation in the clinical findings and identified strains of EHV (A Salib et al. 2016; Azab et al. 2019). On the other hand, other studies could detect EHV in apparently healthy horses (Ata et al. 2020; Meselhy et al. 2019).
A meta-analysis is an epidemiological study designed to systematically assess the results of previous investigations to reach a conclusion about this research topic (Haidich 2010). It includes a combined and quantitative review of a large, frequently complex, and occasionally apparently conflicting body of literature (Moher et al. 2010b). Additionally, the results of the meta-analysis may provide a more accurate estimation of the effect of risk factors or treatment for specific diseases or other outcomes than any individual study participating in the pooled analysis (Moher et al. 2009). Thus, the objective of this investigation is to conduct a meta-analysis on the prevalence of EHV infection in Egypt.
MATERIALS AND METHODS
Ethical approva : Based on guidelines of PRISMA, this study was conducted. Consequently, it is not necessary to have approval from the ethical committee for animal use in scientific research.
Reference horses: The present meta-analysis included all articles focused on the prevalence of EHV infections in Egypt using different techniques. All horses examined, characterized by symptoms of respiratory, neurological, and abortion, were also included. However, the sample size of this study was not limited.
Selection criteria
Inclusion criteria
- Only acceptable papers those are in English language.
- All publications on Equine herpesviruses (EHVs) in Egypt
- A reputable journal publication
- Case-control and cross-sectional studies
- Studies on the seroprevalence of EHV were included.
- Studies imply the prevalence of EHV with any diagnostic technique used.
Exclusion criteria
- Techniques for identifying EHVs other than prevalence.
- Arabic-language publications or languages other than English.
- Preprint and review articles.
Study selection: The objective of this study was to search all publications that had been written about the prevalence of EHV infection in Egypt. We searched the PubMed, Web of Science, Sage, BESCO, Ovid, CABI, Scopus, database with a combination of the following search terms ("EGYPT" "EQUIN HERPESVIRUS") (title/ abstract) ("EQUINE HERPESVIRUS ") (title/ abstract) AND ("EGYPT") (title / abstract) AND ("PREVALANCE" "INCIDENCE") (title/ abstract) OR ("EGYPT") (title / abstract). Preliminary screening of the articles was based on the title and abstract from the earliest data available by May 2024. This procedure was supplemented by manual searching, Google Scholar searching, expert recommendations, and citation reviews. Database outputs were integrated using EndNote software. The standard identification, selection, and eligibility criteria of the selected studies are described (Figure 1).
Data extraction: The extracted data included the year of publication, study area, diagnostic method, sample size, EHV strain, and positive animals (Table 1).
Quality control: According to PRISMA (Moher et al. 2010a), the current meta-analysis was carried out. All available published publications on the assessment of the prevalence of EHV infection in Egypt based on blood sample collection from infected horses were included to reduce publication bias.
Data analysis: First, the prevalence of EHV was estimated and the Chi-square test was used to assess significant variation among infections with different strains of EHV (GraphPad Prism for Windows version 9, USA). The commercial meta-analysis software was used (Comprehensive Meta-Analysis software version 2, Biostat, Englewood, NJ, USA). At random effects model, effect size, 95% confidence intervals, variance, heterogeneity, relative weight, and publication bias were the main tests. To assess the significance of variation between strains of EHV, the chi square test was applied and at p-value of ,0.05 the result was considered significant.
RESULTS
A total of 875 items were identified from database search. After applying the exclusion criteria, 20 acceptable studies were included in this meta-analysis (Table 1, Figure 1). A total of 1760 horses from 20 accepted studies were investigated for EHVs infection. Of these, 740 horses were found positive for EHVs, with a prevalence of 42%. EHV-1 was the most prevalent strain affecting horses in Egypt (p < 0.05).
There was a significant variation in the prevalence of different strains of EHV (p < 0.01). infection rate with EHV-1 was significantly higher than EHV-4 (p < 0.001, Odds ratio: 12.0), EHV-2 (p < 0.001, Odds ratio:7.73), and EHV-5 (p < 0.001, Odds ratio: 14.7). Moreover, the infection rate with EHV-2 was significantly higher than EHV-5 (p < 0.05, Odds ratio: 1.8)
The prevalence of isolated strains was as follows: EHV-1 (492, 66.48 %), EHV-2 (151, 20.40 %), EHV-4 (105, 14.19 %), and EHV-5 (88, 11.89 %). Mixed EHV-1 and EHV-4 infections were predominant. However, EHV-3 was not detected in any of these results.
Meta-analysis
The effect size of the prevalence of EHVs infection at random effect model is presented in Table 2. At random effects, the Z-value was -1.539 (p-value = 0.124). To illustrate the degree of heterogeneity, a forest plot was constructed for random effect. The outcome of event rate with confidence interval of 95%, logit event rate, and relative weight are shown in figures 2-4. The Q-value (373.103), I-squared (95.17), and p-value (0.000) are the outcome of heterogenicity at fixed effect, but not at random effect. Results of publication bias were presented in Figure 5and 6. The funnel plot was asymmetric, and there was no indication of publication bias. The Egger’s linear regression test did not imply a publication bias, and its outcomes were intercept (-3.66), 95% CI (-8.23 to -0.9), t-value (1.96), df = 17.00. The 1-tailed p-value was (0.05), and the 2-tailed p-value was 0.1. The result of Kendall’s tau with continuity correction was -0.18, with a 1-tailed p-value of 0.13 and 2- tailed p-value of 0.26.
The classic fail-safe N proposed that 98000 missing studies are wanted to determine the significance of the results of this meta-analysis. In addition, Orwin’s fail-safe N suggested a -0.47-event rate in observed studies and a 0.50 mean event rate in missing studies.
Table 1. Descriptive data regarding Equine herpesvirus (EHV) infection in horses in Egypt.
Author
|
Location
|
Samples
|
Positive
|
Technique
|
Virus type
|
Signs
|
Amer et al. (2011)
|
Cairo
|
93
|
34
|
Polyclonal antibody pool against EHV-1, 2, and 4
|
EHV-1 (n=3)
EHV-2 (n=17)
EHV-4 (n=7)
EHV-1 and EHV-4 (n=1)
|
Abortion and respiratory signs
|
Kalad et al. (2013)
|
Cairo
|
21
|
9
|
Compliment fixation test
|
EHV-1
|
Respiratory and/or nervous manifestation and contact horses.
|
Al-Shammari et al. (2016)
|
Cairo
|
12
|
12
|
Nested-PCR
|
EHV-4
|
Abortion
|
A Salib et al. (2016)
|
Cairo, Giza, Kafr Elsheikh, Monofeia,
Beni-Suef,
El Sharkia and
Behira
Alexandria
|
182
|
9
|
Indirect ELISA
|
EHV-1
|
Abortions, respiratory diseases, fever and limb edema, Nervous manifestation
|
El Moghazy et al. (2017)
|
Qalubiah
|
77
|
33
|
Indirect ELISA
|
EHV-1
|
No signs
|
(Ghoniem et al. 2018)
|
Cairo
|
152
|
18
|
Multiplex real-time PCR
|
EHV-1 (n=12)
EHV-4 (n=6)
|
Respiratory signs
|
Azab et al. (2019)
|
Cairo, Alexandria, Giza, Sharkia, Gharbia and Monufia
|
192
|
133
|
Virus-specific qPCR
|
EHV-1 (n=64)
EHV-2 (n=63)
EHV-4 (n=5)
EHV-5 (n=37)
|
Abortion, respiratory diseases, fever and limb edema, and nervous manifestation
|
Meselhy et al. (2019)
|
Egypt
|
62
|
12
|
Nested PCR
|
EHV-1
|
No clinical signs mentioned
|
(Ali et al. 2020)
|
Cairo and Giza
|
4
|
4
|
PCR and cytopathic effect
|
EHV-1 (n=4)
|
Abortion and neonatal death
|
Ata et al. (2020)
|
Monufia
|
270
|
173
|
Indirect ELISA
|
EHV-1
|
N0 clinical signs
|
Hassanien et al. (2020)
|
Cairo and Giza
|
20
|
4
|
Consensus nested PCR
|
EHV-1 (n=3)
EHV- 5 (n=1)
|
Abortion
|
Ahdy et al. (2022)
|
Cairo and Giza
|
66
|
25
|
Real-time PCR
|
EHV-1 (gB, ORF33)
|
Abortion (n=14)
Stillbirth (n=3)
Early neonatal deaths (n=2)
Respiratory affections (n=5)
Myeloencephalopathy(n=1)
|
Khattab et al. (2022)
|
Cairo
|
20
|
16
|
Real-time PCR
|
EHV-4
|
Abortion
|
Emam et al. (2022b)
|
Giza
|
72
|
9
|
CPE (Cytopathic effect)
|
(EHV-1)
|
Abortion and
respiratory affections
|
Abdel-Rady et al. (2022)
|
El-Menia, Assiut, Sohage and Luxor
|
115
|
92
|
Multiplex PCR
|
EHV-2 (n=71)
EHV-5 (n=50)
EHV-1 (n=23)
EHV-4 (n=15)
|
Acute early febrile phase of respiratory infection
|
Mohammed et al. (2022)
|
Cairo and Giza
|
80
|
6
|
Real-time PCR
|
EHV-1 (n=1)
EHV-4 (n=5)
|
abortion, respiratory
illness and neurological signs
|
Emam et al. (2022a)
|
Giza
|
72
|
9
|
PCR
|
EHV-l
|
Abortion and
respiratory manifestations
|
El-Zayat et al. (2023)
|
Cairo,Giza, Dakahlia, Sharkia, Gharbia
|
120
|
63
|
PCR
|
EHV-1 (n=48)
EHV-4 (n=15)
Mixed infection (5)
|
Respiratory manifestations and abortion
|
Ali et al. (2024b)
|
Cairo, Dakahlyia and Qalyubia
|
80
|
53
|
Consensus PCR
|
EHV-1 (n=29)
EHV-4 (n=24)
Mixed infection (5)
|
No
|
Ali et al. (2024a)
|
Cairo, Dakahlyia and Qalyubia
|
50
|
26
|
Consensus PCR
|
EHV-1
|
Abortion
|
Table 2. Final Meta-analysis results of the effect of size and test of null (2-tail) for 19 studies on the prevalence of Equine herpesvirus in Egypt.
Model
|
Effectsizeand95% Confidence Interval
|
Testofnull(2-Tail)
|
Number of studies
|
Point estimate
|
Lowerlimit
|
Upperlimit
|
Z-value
|
P-value
|
Random
|
20
|
-0.445
|
-0.11
|
0.122
|
-1.539
|
0.124
|
DISCUSSION
Egypt is one of the most famous countries and centers for breeding and exportation of pure Arabian horses (Kalad et al. 2013). In the absence of any previous systematic meta-analysis on the prevalence of EHV infection in Egypt, we conducted this study. This meta-analysis provides the results of electronic and print sources of peer-reviewed publications without restrictions on the publication date. Conference proceedings, technical reports, and other grey literature were not included in this meta-analysis.
Twenty studies fulfilled the selection criteria for the present study. In these studies. A total of 1683 horses were tested for EHV infection with prevalence of 42%. The prevalence of EHV infection varied widely among selected studies. This finding may be attributed to the used diagnostic test, age and gender of tested horses. The high prevalence reflects the importance of the EHV infection to cause multiple clinical manifestations, especially respiratory signs and abortion. Similar prevalence has been recorded in Tunesia (Badr et al. 2022). In the present study, the prevalence varied among studies even with using the same diagnostic technique. The prevalence of EHV-1 was the highest among the Arabian horses (Abdel-Rady et al. 2022; Ahdy et al. 2022). This finding is supported by findings of outbreaks caused by EHV-1 (El-Hage et al. 2021).
The study population and presence of risk factors are determinants of the prevalence of infectious diseases (Buitrago-Garcia et al. 2022). Variables such as age and sex of the horses studied have been linked to a higher risk of EHV infection. Young foals are more likely to be infected with EHV-2/-5 than adult horses (Hue et al. 2014), whereas equids aged 3–8 years have a higher prevalence of EHV-1/-4 than those younger than 3 years (Worku et al. 2024). Gender differences have also been observed, with males more likely to contract EHV-1-2 (Bolfa et al. 2017). On the other hand, many researchers have reported higher rates of EHV-1 and -4 among females than among males (de Souza et al. 2017; Negussie et al. 2016).
Clinically, 16 out of 20 eligible studies detected EHV in horses with various respiratory manifestations, abortion, and myeloencephalopathy. Similar findings have been reported globally (Kapoor et al. 2014; Sutton et al. 1998; Van Maanen 2002). The EHV-1 infection is a cause for upper respiratory tract signs in young horses and abortion in mares (Smith et al. 2004). However, myeloencephalopathy in adults and placental damage without abortion during early gestation have been also demonstrated (Allen et al. 1999). The EHV-4 also induces mainly respiratory infections in young and rarely causes abortion (Reed and Toribio 2004). The signs of respiratory disease associated with EHV infection are difficult to detect but may be observed as an outbreak (Reed and Toribio 2004). However, the genotype of EHV-1 did not affect clinical signs (Pusterla et al. 2020).
The present meta-analysis included 20 studies, of which 14 used molecular techniques were used for the diagnosis of EHV. However, the remaining studies used only screening tests. This finding may reflect the potential of studies using this technique. The multiplex real-time PCR is a convenient and rapid tool for investigating the clinical relevance of EHV-2 and EHV-5 (Fürer et al. 2022). Meanwhile, Other techniques were found to be reliable for detecting different strains of EHV (Lang et al. 2013; Nordengrahn et al. 2001).
Based on the results of meta-analysis, the study of Ata et al. (2020) provided a relative weight of 20.34 %, whereas the small studies by Al-Shammari et al. (2016) and Ali et al. (2020) are given approximately 0.16 % and 0.15% of the relative weight, respectively. It is known that the common effect is well assessed by larger studies but not by small studies. Studies with small sample size had a negligible effect on the total value. Consequently, larger studies with smaller standard errors have greater weight than those of smaller studies with large standard errors. The present meta-analysis provided Z-values of -1.377 (p = 0.168) and -1.539 (p = 0.124). The Z-value here does not add to the results, as it is not the effect size, but only indicates the data distribution (Hak et al. 2016).
Regarding heterogeneity, the Q-statistic and I2 for the prevalence of EHV were 373.103 and 95.17, respectively (p-value < 0.000). The Q-statistic includes the observed dispersion, while the null hypothesis for heterogeneity proposes that the studies assign a common effect size. Consequently, it is assumed that the degrees of freedom are equal to the Q-statistic (Thompson 1994). However, if Q-statistic provides no effect size dispersion, I2 and tau-squared can provide alternative good interpretation (Schulz et al. 1995).
The I2 concludes that the definite differences in effect sizes for 99 % of the variance among the studies, and only 1% of the observed variation can be predicted by means of random error. The tau-squared value for EHV infection was 1.383, which is the variance among studies and is utilized to calculate the weights. It has been stated that the I2 can be used to measure the level of heterogeneity in meta-analysis, but the eyeball test is a less formal substitute to measure the heterogeneity (Huedo-Medina et al. 2006).
Heterogeneity analysis usually proves how the effect width varies among studies. This statistical test explains the difference among studies due to differences between the studies or to sampling errors (Borenstein et al. 2021). Heterogeneity tests are performed to determine the conformity of the normal distribution of effect sizes. Considering heterogeneity, the null hypothesis is that the effect will be zero for both fixed and random effects. Hedges' g/standard error for the relevant model is usually used to determine the z-value, which is used to check the null hypothesis (Higgins JP 2019). It has also been stated that the p-value is not an effect size, and therefore, is not a measure of the magnitude of heterogeneity. In this case, a low p-value indicates that there is probably some (unidentified) degree of heterogeneity (Duffield et al. 2008).
Regarding publication bias, publication bias is evident in reports with small sample size (Joober et al. 2012). Thus, detecting bias is an important issue as it has determinantal effect on the conclusion of systematic meta-analyses (Sutton et al. 2000). Funnel plot, an indicator usually used to decide the evidence of bias. In this plot, the effect size is usually shown against standard errors or precision (Light and B. Pillemer 1986). In the present study, the funnel plot was asymmetric, and there was no indication of publication bias. Moreover, the Egger’s test confirmed absence of publication bias (intercept: -3.66, 95% confidence interval: - 8.23 to - 0.9; t-value: 1.96; df: 17.00). From the statistical meta-analysis, lack of bias is identified by zero level of regression slope (Rothstein HR 2005). If the Begg test has strong correlation, this indicates presence of publication bias (Begg and Mazumdar 1994).
Trim and fill test evaluates the total effect size and tests publication bias (Duval and Tweedie 2000). A repeated technique was used to exclude small studies at the extreme ends of the positive end of the funnel plot. The trimming and filling processes were repeated until the funnel plot was symmetric (Duval 2005). In the present result, the trim-and-fill finding appears as the closed dots indicating the missing studies (no studies trimmed), and the open dots indicate the observed studies (about 20 studies) imputed, which depend greatly on the selected estimator (R0, L0, or Q0) for imputing missing studies and its result in an adjusted correlation from -0.19 to 0.034 (95% CI).
The fail-safe test suggests that 980000 missing studies were required to conclude the result of study is significant (p = 0.000). Additionally, Orwin’s fail-safe N suggests a 0.47 event rate in observed studies and a 0.50 mean event rate in missing studies. Even though they are usually used in meta-analysis, these publication bias assessments could have type I error rate and/or low power (Peters et al. 2006; Peters et al. 2007; Rücker et al. 2008; Sterne et al. 2000; Terrin et al. 2003).
Conclusion : The results of the present meta-analysis indicate a high prevalence of EHV infection in Egypt, particularly EHV-1. Therefore, more attention should be paid to prevention and control of this disease.
Conflict of interest: Authors declare that there is no conflict of interest.
Funding: This work was supported by the Deanship of Scientific Research, Vice Presidency for Graduate Studies and Scientific Research, King Faisal University, Saudi Arabia (funding number: A304).
Data availability: Data are available on request.
Authors, contribution: Authors contributed equally to this paper.

Figure 1. Results of the literature search and inclusion regarding prevalence of Equine herpesvirus (EHV) infection in Egypt.

Figure 2. Forest Plot on the prevalence of EHV infection shows the event rate, 95% confidence interval, Z- value, P- value, and relative weight of 20 observed studies.

Figure 3. Forest Plot of the prevalence of EHV infection shows the logit event rate, 95% C, standard error, and variance on the random effect model of 20 observed studies.
Figure 4. Forest Plot of the prevalence of EHV infection shows the weight on the random effect model of 20 observed studies.

Figure 5. Funnel plot of the prevalence of EHV infection shows standard error by logit event rate on the random effect model of 20 observed and imputed studies.

Figure 6. Funnel plot of the prevalence of EHV infection shows precision by logit event rate on the random effect model of 20 observed and imputed studies.
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