Necrotizing gingivitis in patients with and without HIV: a systematic literature review and meta-analysis

Gengivite necrosante em pacientes com e sem HIV: uma revisão sistemática da literatura e meta-análise

ABSTRACT

Necrotizing periodontal diseases are historically established conditions that gained prominence during the First World War. Their etiology was linked to poor oral hygiene, opportunistic infections, and stress. Characterized by severity and debilitation, the disease progresses rapidly with necrotic ulcers in periodontal tissues, resulting in pain, tissue bleeding, and a foul odor. Due to the distinctive features and accelerated evolution of periodontal conditions in immunocompromised patients, individuals with Human Immunodeficiency Virus leading to Acquired Immunodeficiency Syndrome are classified as at-risk patients for the development of Necrotizing periodontal diseases. Thus, this review aims to compare the prevalence of gingivitis and necrotizing periodontitis in AIDS patients in comparison to the immunocompetent population. Additionally, it seeks to evaluate how the state of immunosuppression alters the oral cavity and provides clarity regarding the impact of AIDS on periodontal diseases. This study adhered to the methodological protocols of a systematic review as outlined in the Cochrane Handbook. The search strategy was implemented across the following databases: Pubmed, Cochrane Library, Scopus, Web of Science, and Embase. The association of necrotizing periodontal diseases in HIV+ individuals was investigated through a systematic analysis of the literature.

Indexing terms
Gingivitis, necrotizing ulcerative; HIV; Periodontal diseases

RESUMO

As doenças periodontais necrosantes são condições historicamente estabelecidas e ganharam destaque no período da primeira guerra mundial, sua etiologia estava ligada a falta de higiene oral, infecções oportunistas e quadros de estresse. De caráter grave e debilitante, a doença progride rapidamente com úlceras necróticas em tecido periodontal, gerando dor, sangramento dos tecidos e odor fétido. Em virtude de suas características e da evolução acelerada dos quadros periodontais em pacientes imunocomprometidos, pacientes portadores do vírus da imunodeficiência humana que desenvolvem a síndrome da imunodeficiência adquirida são classificados como pacientes de risco para desenvolvimento de doenças periodontais necrosantes. Dessa forma, a presente revisão busca comparar a prevalência de gengivite e periodontite necrosante em pacientes com AIDS em relação a população imunocompetente, bem com avaliar como o estado de imunossupressão altera a cavidade bucal; esclarecer a respeito do impacto da AIDS nas doenças periodontais. O presente estudo foi conduzido seguindo os protocolos metodológicos da revisão sistemática descritos no Cochrane Handbook. A estratégia de busca foi aplicada nas bases de dados: Pubmed, Cochrane Library, Scopus, Web of Science e Embase. Verificou-se a associação de doenças periodontais necrosantes em portadores de HIV+ por meio de uma análise sistemática da literatura.

Termos de indexação
Gengivite ulcerativa necrosante; HIV; Doenças periodontais

INTRODUCTION

Necrotizing Periodontal Diseases (NPDs) are historically established conditions that garnered attention during the First World War when more severe cases of the disease came to light. Referred to as ‘trench mouth’ during that period, Necrotizing Gingivitis (NG) was etiologically linked to poor oral hygiene, opportunistic infections, and the intense stress experienced by soldiers. With a severe and debilitating nature, the disease progresses rapidly, manifesting as necrotic ulcers in periodontal tissue, causing significant pain, tissue bleeding, and foul odor [¹,²].

Due to its prominence in the era preceding the development of antibiotics, NPDs were typically addressed with hydrogen peroxide and improved oral hygiene. However, such measures proved insufficient for precise control of the conditions, and effective reversal began with the use of penicillins [³,⁴].

It is important to highlight that, following the new classification of periodontal diseases, the term ‘ulcerative’ is no longer employed in categorizing necrotizing periodontal diseases, as ulceration is considered secondary to necrosis. Consequently, the terms Necrotizing Ulcerative Gingivitis (NUG) and Necrotizing Ulcerative Periodontitis (NUP) have been replaced by Necrotizing Gingivitis (NG) and Necrotizing Periodontitis (NP). Furthermore, NG and NP can progress to more severe forms, such as Necrotizing Stomatitis (NS), when the necrotic tissue extends beyond the mucogingival junction, and ‘Noma’ in its advanced stage, both of which are now part of the NPDs group [⁵,⁶].

Effective therapy, coupled with enhanced knowledge of oral hygiene, has rendered NG and NP rare diseases with a prevalence of less than 1% in the population. However, individuals with nutritional deficits, stress conditions, and compromised immune systems become susceptible [⁷].

Due to their characteristics and the rapid progression of periodontal conditions in immunocompromised patients, individuals carrying the Human Immunodeficiency Virus (HIV) and developing Acquired Immunodeficiency Syndrome (AIDS) are classified as at-risk patients for the development of Necrotizing Gingivitis and Necrotizing Periodontitis (NP). Besides immunological status, additional factors such as psychological elements, including a loss of motivation for oral care, or nutritional deficiencies, further elevate the risks of NG and NP [¹,⁸].

Despite this historical correlation, the literature presents conflicting findings regarding the prevalence of necrotizing diseases in the HIV+ population. Moreover, the constant updates in knowledge about AIDS patients often render this causal relationship outdated, necessitating more objective parameters for the classification of the at-risk population [⁷,⁹].

Thus, this review aims to compare the prevalence of NG and NP in patients with AIDS in comparison to the immunocompetent population. Seeking to characterize a deeper understanding of the etiology of these pathologies, the review also aims to provide an epidemiological perspective on the relationship between HIV and NDs.

METHODS

The scientific manuscript diligently traversed each stage of the 2020 PRISMA update, rigorously adhering to the methodological protocols for systematic reviews outlined in the Cochrane Handbook [¹⁰,¹¹]. The chosen methodological approach was duly registered on the PROSPERO platform under registration number CRD42022321243. The search strategy, rooted in Medical Subject Headings (MeSH), was crafted as “(Patients, HIV and ‘Gingivitis, Necrotizing Ulcerative’)”, systematically expanded with the suggested entry terms in the MeSH interface. This comprehensive search strategy was then meticulously applied across various databases, including Pubmed, Cochrane Library, Scopus, Web of Science, and Embase. Notably, in Embase, MeSH terms were replaced with Emtree terms. Furthermore, no language or publication date restrictions were imposed, and the search was concluded in February 2024.

Regarding inclusion criteria, selected articles exclusively involved human samples and reported on adult patients aged over 18 years and under 60 years with HIV, explicitly mentioning the incidence of NG. Additionally, these studies incorporated patients without clinical manifestations of HIV as a defined control group. The exclusion criteria thoughtfully ruled out articles evaluating diabetic patients, those lacking patients with symptoms of pain and discomfort, and those incorporating patients with other types of immunosuppression. The systematic selection process adhered meticulously to the PRISMA protocol, systematically progressing through the scrutiny of titles, abstracts, and subsequently, full texts.

In terms of the bias risk analysis, this evaluation was conducted using the Newcastle-Ottawa scale (total score) for observational studies and the Methodological Quality. The risk of bias and the qualitative synthesis were organized into a table using Excel (Table 1). The quantitative datas were exploited also using Excel and with the following variables: author and year; group (with or whitout HIV); the number of patients in the group; the number of patients who presented with necrotizing gingivitis.

The data were dichotomized into comparable groups based on the similarity of the sample profile and outcome presentation. When feasible, a meta-analysis was conducted using RevMan 5.4 software, employing the Odds Ratio measure and a random-effects model.

RESULTS

The present review initially identified 483 results in the search, of which only 14 met all the proposed inclusion criteria. After the initial screening, the selected findings had their references evaluated to identify any additional relevant literature, resulting in the inclusion of two more studies. The article selection process is outlined in figure 1.

Figure 1
PRISMA Flowchart of included studies.

The 16 retrieved articles were observational in nature and assessed using the Newcastle-Ottawa Scale tool. Most articles had a high risk of bias; however, those used for the meta-analysis had a moderate level of bias. The major shortcomings in the studies were related to the correct division of assessed groups and the lack of standardization in HIV and NG diagnosis. Murray’s article received a zero score due to its classification, which currently does not suit HIV studies.

The articles varied in publication year from 1988 to 2011. Clinical findings and diagnostic and prognostic observations reported in the selected articles were summarized along with the bias risk scores in table 1.

Table 1
Qualitative Synthesis and Risk of Bias analysis of included studies.

Author (Year)	Qualitative Synthesis	Newcastle-Ottawa Score
Begg et al. (1997) [12]	Oral lesions may be associated with HIV;	6
	NG is associated with AIDS progression;
	NG is less indicative than oral candidiasis and Kaposi’s sarcoma;
	The presence of lesions alone is not a sufficient predictor of HIV.
Laskaris et al. (1992) [13]	Clinical manifestations of HIV infection can have oral lesions as their first and only clinical presentation;	2
	NG is an early manifestation in seropositive patients.
Hartnett and Shiloah (1991) [14]	Rapidly progressing periodontal disease may be related to HIV.	2
	20% of HIV patients present with NG.
	Local debridement, oral hygiene, and mouthwash are primary treatment measures.
	The use of systemic antibiotics should be avoided to reduce the risk of opportunistic infections.
Winkler et al. (1992) [15]	Chlorhexidine is important for treating patients with periodontal lesions associated with HIV.
	Debridement, antimicrobial therapy, immediate follow-up, and regular maintenance are crucial for treating oral lesions associated with HIV.
	Metronidazole is particularly effective in managing these lesions.
Schulten et al. (1988) [16]	Sarcoma de Kaposi is the primary oral lesion associated with HIV.	3
	Necrotizing periodontitis has a weak association with HIV.
Murray et al. (1989) [17]	HIV+ individuals and NG have an uncertain relationship with advanced progression of periodontal disease.	0
	New studies are necessary to determine whether the microbiota of HIV-associated periodontal disease is the same or different from NG.
Rowland et al. (1993) [18]	There are significant differences in lymphocyte counts in HIV-seropositive individuals with necrotizing periodontal lesions.	4
Grbic et al. (1995) [19]	In the study exclusively involving homosexual men, seropositive individuals had a lower number of CD4+ lymphocytes and white blood cells.	4
	The lower number of CD4+ lymphocytes and white blood cells is associated with GUN lesions and a decrease in circulating CD4+.
	The use of different medications for HIV infection has a profound effect on the periodontium.
	It becomes complex to determine whether the lesions are associated with HIV or the consumed medications.
Thompsonet al. (1992) [20]	The marginal gingivitis characteristic of HIV-associated gingivitis does not correlate with the depression of helper T lymphocytes.	4
	The absence of previously reported HIV-I-associated oral diseases raises doubts about the interpretation of data concerning specific cause-and-effect relationships.
Horning (1995) [21]	NG is associated with HIV and linked to oral hygiene, emotional stress, diet, inadequate sleep, recent illness, smoking, age under 21, and Caucasian race.	3
Kroidl (2005) [22]	Advanced immunosuppression is related with periodontal disease.	6
	Before Highly Active Antiretroviral Therapy (HAART), HIV patients had a high rate of oral candidiasis and hairy leukoplakia manifestations.
	These manifestations were associated with highly suppressed CD4 counts.
Sontakke et al. (2011) [23]	The CD4+ cell count and viral load serve as markers for HIV-related disease progression.	6
	Periodontal disease manifested in less severe immunosuppression, with CD4 levels measuring 290 cells/mm³.
	A decrease in salivary flow can result from HIV infection, anti-HIV medication side effects, or association with a major salivary disorder.
Rowland (1999) [24]	Immunosuppression is the predominant factor for the development of GN.	4
	Immunosuppression may be associated with all predisposing factors.
	The signs and symptoms of GN typically resolve within a few days after appropriate treatment.
Mataftsi (2011) [25]	HAART transformed HIV infection into a chronic condition.	2
	HAART led to an increase in CD4+ cell count, decreased HIV RNA levels, and extended AIDS-free survival.
	Inflammation is considered a risk factor for HIV infection.
	Studies indicate that HIV is present in the saliva of patients at very low levels.
Ramírez-Amador et al. (2003) [26]	GN are lesions strongly associated with HIV.	3
	Over the years, the profile of these lesions has undergone changes.
	Assistance plays a crucial role in treatment, and HAART has improved the clinical presentation of these lesions.
Ferreira et al. (2007) [27]	Patients with CD4+ counts below 200 cells/mm³ had a higher prevalence of oral lesions.	3
	The use of Highly Active Antiretroviral Therapy (HAART) reduced the occurrence of these lesions.

Only 11 articles provided quantitative data that could be extracted regarding the correlation between HIV and NG. These data are presented in table 2.

Table 2
Quantitative analysis of included studies.

Author (Year)	Group	n by Group	n with GN
Begg et al. (1997) [12]	CD4>200 cells/µl	90	4
	CD4<200 cells/µl	41	4
Laskaris et al. (1992) [13]	HIV+	77	11
Schulten et al. (1989) [16]	ARC	53	4
Murray et al. (1989) [17]	Homosexual Man	45	NR
	Heterosexual Man	19	NR
Rowland et al. (1993) [18]	HIV+	7	2
	HIV-	13	13
Grbic et al. (1995) [19]	HIV +	77	4
	HIV -	45	0
	HIV + e PCU	81	0
	HIV - e PCU	48	2
Thompson et al. (1992) [20]	Peripheral helper T lymphocytes (<400 cells/mm³)	390 no separationof groups	21
	Peripheral helper T lymphocytes (>400 cells/mm³)		7
Kroidl (2005) [22]	CD4: <200 cells/µl	39	4
	CD4: 200-500 cells/µl	57	1
	CD4: >500 cells/µl	38	0
	HIV-RNA: <1.000 copy/ml	94	2
	HIV-RNA: >1.000 copy/ml	42	3
Sontakke et al. (2011) [23]	CD4 <200	28	0
	CD4 200-500 cells/mm³	10	2
	CD4 >500 cells/mm³	15	0
Ramírez-Amador et al. (2003) [26]	AIDS	48	3
Ferreira et al. (2007) [27]	HIV+	1230	9

A meta-analysis was conducted comparing CD4 cell concentrations with the diagnosis of GN. The present analysis shows an Odds Ratio of 2.20 with a confidence interval from 0.22 to 21.6. Heterogeneity among the studies, as indicated by the I² test, was 62%. The comprehensive analysis can be reviewed in figure 2.

Figure 2
Florest Plot of Meta Analysis. Comparison of CD4 cell concentration with diagnosis of NG.

DISCUSSION

Oral lesions alone do not constitute sufficient evidence to predict a clinical manifestation of HIV infection, with their diagnosis better established through the correlation with other syndromic signs [¹²]. However, George Laskaris et al. [¹³] report that AIDS manifestations may not exhibit noticeable symptoms in the early stages of infection, and oral lesions could be the initial and sole oral presentations of the disease. Several oral findings may be associated with infection, and among the most common are oral candidiasis, necrotizing ulcerative gingivitis, hairy leukoplakia, and linear gingival erythema [¹²,¹⁴]. Schulten et al. [¹⁶] found Kaposi’s Sarcoma as the only oral manifestation of HIV in their report.

Murray [¹⁷] employed HIV+ homosexual men and HIV- heterosexual men as a control group for comparative analysis in his studies. Research conducted prior to gaining a deeper understanding of HIV held prejudiced information. Thus, it is crucial to highlight that perceptions of oral lesions and HIV have evolved over the years. Recent studies show that the profile of HIV/AIDS has changed, with a rise in cases among women, heterosexuals, individuals aged 15 to 24, adults over 50, and those with lower educational levels [²⁸].

Among oral lesions strongly associated with AIDS, Necrotizing Ulcerative Gingivitis (NUG) and Necrotizing Ulcerative Periodontitis (NUP) have gained prominence due to their rapid progression and association with debilitating factors [⁴,²⁹]. Our findings demonstrate that this correlation is linked to the immune system deficiency caused by HIV infection in the body, leading to a higher propensity for lesion development [¹⁸,¹⁹,³⁰]. However, according to Laskaris et al. [¹³], NUG is a possible early manifestation of AIDS even in the initial stages of infection, when immunosuppression is not significant [³¹].

It is essential to emphasize that compromised immune cells do not necessarily signify the progression of periodontal disease but rather serve as a potential etiological source [^{23 21}]. Nevertheless, the origin of periodontitis in HIV patients remains largely uncertain; some studies suggest the possibility of an HIV-associated periodontitis having a microbiota distinct from the traditional one, indicating a need for further research [¹⁷].

From this perspective, a concentration of viable TCD4 cells below 200 already indicates compromised immune system function [⁹,³²], and this threshold was utilized in studies by Kroidi [²²], Begg et al. [¹²], and Sontakke et al. [²³]. At this level of immunological compromise, the characteristic signs and symptoms of HIV may manifest more prominently [³³]. However, no statistical correlation with NUG/PUN was identified in the screened studies. The study by Sontakke et al. [²³] did not find any indication that the low concentration of CD4 cells acts as a predictor of Necrotizing Periodontal Diseases (NPDs). It is essential to highlight that the present analysis exhibits high sample heterogeneity and compares few publications, underscoring the need for primary studies to standardize the level of immunocompromise, as well as the assessment of NUG/PUN to validate these findings.

It is known that periodontal inflammation linked to immunosuppression can trigger ulcerative periodontal diseases, such as NUG/PUN and Linear Gingival Erythema (LGE) [²²]. Among the treatments for NPDs, the removal of necrotic tissue (debridement) and the crucial control of biofilm through regular oral hygiene, coupled with chlorhexidine and iodopovidone rinses, are highlighted [¹⁵,¹⁹,²³]. Additionally, immediate follow-up and regular long-term maintenance are of great value for the treatment and prevention of lesion recurrence. The implementation of appropriate treatment allows for the disappearance of clinical signs and symptoms within the first few days [²⁴].

Before the era of highly active antiretroviral therapy (HAART), lesions such as oral hairy leukoplakia (OHL) and oral candidiasis were easily discernible in HIV patients [²²]. Following the implementation of HAART, a notable surge in CD4+ cell count was observed, coupled with a reduction in HIV RNA levels. This extension of the period during which patients remained free from clinical manifestations of AIDS characterized HIV infection as a chronic condition, marked by the persistent presence of the virus in the infected host [²⁵].

Studies indicate that HIV is also detectable in the saliva of patients, albeit at very low levels—lower than those found in the blood. HIV infection is known to contribute to a reduction in salivary flow, either as a side effect of anti-HIV medication or due to its association with salivary gland diseases [²³,²⁵]. It is crucial to highlight that the use of various medications such as antibiotics, antifungal agents, and antivirals can significantly impact periodontal tissue due to alterations in the microbiota [¹⁹].

The study by Hartnett and Shiloah [¹⁴] suggests the presence of microorganisms associated with HIV-related gingivitis and periodontitis, stemming from immunodeficiency in HIV+ patients. This imbalance between host immune response and aggression potentially exacerbates the progression of periodontal disease. Therefore, a correlation can be asserted between periodontal attachment loss and a reduction in TCD4+ cell count, as the attenuation of the immune response in HIV+ patients, combined with intrinsic host factors, poses an additional risk of periodontal destruction [²⁵,³⁴].

Throughout the years, the clinical profile of oral lesions associated with HIV has undergone significant changes. Notably, there has been a decrease in the prevalence of most of these lesions since the introduction of highly active antiretroviral therapy (HAART), improved medical care conditions, and increased usage of prophylactic medications to prevent secondary opportunistic infections related to AIDS. The enhanced immune system has resulted in a reduction in the occurrence of opportunistic infections and neoplasms. Additionally, the decline in periodontal diseases as a consequence of these therapies has contributed to an improved quality of life for patients with HIV [²⁶,²⁷,³⁵].

CONCLUSION

Based on the presented information, it can be concluded that certain oral manifestations were strongly associated with the presence of HIV, especially Necrotizing Periodontal Diseases (NPDs) like Necrotizing Gingivitis (NG) due to immunosuppression. Following the implementation of highly active antiretroviral therapy (HAART), a significant increase in TCD4+ cell count was observed, along with a decrease in HIV RNA levels. This led to a notable decrease in the prevalence of oral lesions associated with HIV, including a lower incidence and severity of NG. Consequently, this improvement has contributed to a better quality of life for these patients.

How to cite this article

• Lorentz BCS, Guimarães LFC, Barra SG, Candido CBSA, Paiva DFF. Necrotizing gingivitis in patients with and without HIV: a systematic literature review and meta-analysis. RGO, Rev Gaúch Odontol. 2024;72:e20240039. http://dx.doi.org/10.1590/1981-86372024003920240021

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Edited by

• Assistant editor: Luciana Butini Oliveira

Publication Dates

• Publication in this collection
  11 Nov 2024
• Date of issue
  2024

History

• Received
  14 Mar 2024
• Reviewed
  08 June 2024
• Accepted
  11 Sept 2024