Role of viruses in periodontitis: An extensive review of herpesviruses, human immunodeficiency virus, coronavirus-19, papillomavirus and hepatitis viruses

Table 1 Key information on the human herpes virus types, the main target cells, their oral and systemic pathologies

Human herpes virus	Main target cells	Oral pathology	Systemic pathology
HHV-1 and 2 (HSV 1 and 2)	Mucoepithelial cells (orofacial and genital tract)	Primary herpetic gingivostomatitis. Recurrent herpetic gingivostomatitis. Chronic herpetic gingivostomatitis. Herpes labialis. Increased risk of periodontitis	Genital ulcers
HHV-3 (VZV)	Mucoepithelial cells and T cells (orofacial and any skin or mucosa of the body)	Possible oral vesicles and ulcers, increased risk of periodontitis	Primary infection: Varicella (chicken pocks). Recurrent infection: Herpes zoster (shingles)
HHV-4 (EBV)	Mucoepithelial cells and B cells	Hairy leukoplakia, leukoplakia, nasopharyngeal carcinoma, ulcerations and palatal petechiae, oral lymphoma, increased risk of periodontitis	Infectious mononucleosis, lymphoma
HHV-5 (CMV)	Monocytes, fibroblasts, lymphocytes and epithelial cells	Oral vesicles and ulcers, increased risk of periodontitis	Infectious mononucleosis
HHV-6	T cells, epithelial cells, monocytes, fibroblasts and more	Unknown
HHV-7	T cells, epithelial cells, monocytes, fibroblasts and more	Unknown
HHV-8	Not identified	Ulcers and tumors	Kaposi’s sarcoma

EBV: Epstein-Barr virus; CMV: Cytomegalovirus; HHV: human herpes virus, HSV: Herpes simplex virus; VZV: Varicella-zoster virus.

Table 2 A list of systematic reviews and meta-analyses on the association between human herpesviruses and periodontitis

Ref.	Study design	Findings	Conclusion	Reported statistical significance
Jakovljevic et al[27], 2022	Umbrella review including six meta-analyses on HHVs detection in MP and apical periodontitis of endodontic origin (APEO)	MP risk increased with subgingival HHVs. The connection was robust (OR > 3.0), although confidence intervals were broad, heterogeneity was high, and studies were small. However, systematic reviews of APEO and HHVs found no significant relationships	There was a substantial correlation between HHVs and MP, but not APEO, according to low-quality, highly unclear research	MP: Yes; APEO: No
Arduino et al[26], 2023	Meta-analysis of eight observational studies on HSV-1 in endodontic peri-apical lesions including 194 adult patients	Pooled HSV-1 prevalence was 4.8% (95%CI: 2.0%–11.4%; adjusted for small-study effect); 8.1% (95%CI: 4.4%–14.5%, quality-adjusted); and 6.8% (95%CI: 3.6%–11.0%, random-effects)	3%–11% of periapical disease patients had HSV-1 colonization. Such data do not suggest HSV-1 causes the onset and progression of periodontitis	No
Arduino et al[25], 2022	Meta-analysis of twelve case–control and cross- sectional studies (738 cases, 551 controls), investigating HSV-1 in subgingival plaque/crevicular fluid and periodontitis	For any type of periodontitis, the pooled ORs were 44 (95%CI: 1.9–10.2); for chronic periodontitis, they were 28 (95%CI: 1.0–8.3); and for aggressive periodontitis, they were 118 (95%CI: 5.4–25.8)	HSV-1 was associated with periodontitis	Yes
Maulani et al[21], 2021	Meta-analysis of studies on EBV, involving 1354 periodontitis patients and 819 healthy controls	When subgingival EBV was found, there was an increased incidence of periodontitis: OR = 7.069 (95%CI: 4.197–11.905, P < 0.001)	An elevated risk of periodontitis is linked to a high frequency of EBV detection	Yes
Roca-Millan et al[22], 2021	Meta-analysis of five researches on EBV and peri-implantitis. The study included 274 patients (125 men and 149 women) and 388 implants (197 healthy, 166 peri-implantitis, and 25 mucositis)	In the peri-implant sulcus, there was no significant difference in EBV presence between peri-implantitis and healthy implant groups (OR = 4.14; 95%CI: 0.93-18.37; P = 0.06)	EBV prevalence in the sulcus was not statistically different between peri-implantitis and normal implant groups	No
Li et al[28], 2017	Meta-analysis of twelve case-control studies on the presence of HHVs in AgP involving 322 patients and 342 controls	EBV showed substantial connection with AgP, however publication bias was present (10 studies: OR = 6.11, 95%CI: 2.13–17.51, P = 0.0008). HCMV and HSV-1 also showed significant associations (12 studies: OR = 3.63, 95%CI: 2.15–6.13 P = 0.009; 4 studies: OR = 19.19, 95%CI: 4.16–79.06, P < 0.001). Relation between HSV-2 and AgP was inconclusive (2 studies: OR = 3.46, 95%CI: 0.51–23.51, P = 0.20)	AgP showed strong associations with EBV, HCMV, and HSV-1. But there was a lot of heterogeneity among the studies	Yes
Zhu et al[29], 2015	Meta-analysis of 12 studies (including 552 cases and 371 controls) investigated the association between HHVs and chronic periodontitis	EBV: 12 studies (OR = 5.74, 95%CI: 2.53–13.00, P < 0.001). HCMV: 10 studies (OR = 3.59, 95%CI: 1.41–9.16, P = 0.007). HSV: 2 studies (OR = 2.81 95%CI: 0.95–8.27, P = 0.06). HHV-7: 1 study (OR = 1.00, 95%CI: 0.21–4.86)	Chronic periodontitis was highly correlated with both HCMV and EBV. Inadequate evidence was found for HHV-7 and HSV	EBV: Yes; HCMV: Yes; HSV: No; HHV-7: No
Botero et al[24], 2020	Meta-analysis of 32 studies on HCMV in periodontitis (26 studies involving periodontitis and 6 involving apical periodontitis)	Significantly elevated periodontitis risks with subgingival HCMV (OR = 5.31; 95%CI: 3.15-8.97). HCMV was not linked to apical periodontitis (OR 3.65; 95%CI: 0.49-27.10)	HCMV was significantly associated with periodontitis but not with apical periodontitis	Periodontitis: Yes; Apical periodontitis: No
Gao et al[23], 2017	Meta-analysis of 21 case–control studies (including 995 patients and 564 healthy people) on the association between EBV and periodontitis	Significant differences were found in the odds of periodontitis and EBV detection (OR = 6.199, 95%CI: 3.119–12.319, P < 0.001)	An elevated risk of periodontal diseases was connected with a high prevalence of EBV	Yes
Alzahrani[19], 2016	Systematic review of 12 studies on the association between HHVs and risk of AgP and AP		In contrast to healthy individuals, HHVs (HSV, CMV, and EBV) levels were elevated and linked to AgP and AP	Yes
Jakovljevic et al[30], 2014	Meta-analysis of 17 cross-sectional studies on the association of HCMV and EBV with apical periodontitis	No statistically significant relationship between the presence of HCMV and EBV messenger RNA transcripts (P = 0.083 and P = 0.306, respectively) and the clinical features of apical periodontitis	HCMV and EBV were common in symptomatic and large-size periapical lesions, but not statistically significant	No

HSV: Herpes simplex virus; AgP: Aggressive periodontitis; MP: Marginal periodontitis; APEO: Apical periodontitis of endodontic origin; EBV: Epstein-Barr virus; HCMV: Human cytomegalovirus; AP: Advance periodontitis; HHV: Human herpesvirus; OR: Odds ratio.