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Review paper

Relationship of oral candidiasis with salivary lysozyme and lactoferrin in HIV-positive patients: a systematic review

Paria Motahari
1

1.
Department of Oral Medicine, Faculty of Dentistry, Tabriz University of Medical Sciences, Tabriz, Iran
HIV AIDS Rev 2021; 20, 1: 17-20
Online publish date: 2021/04/12
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- HIV-00297-Motahari.pdf  [0.60 MB]
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Introduction

Oral candidiasis is one of the most common fungal infections, which affects the oral mucosa [1]. Ninety percent of patients with acquired immune deficiency syndrome (AIDS) suffer from oropharyngeal candidiasis in many stages of their disease. Candida albicans is the major cause of oral candidiasis in patients with human immunodeficiency virus (HIV) and AIDS. With the development of HIV infection, despite the use of antifungal drugs prophylaxis, oral candidiasis becomes a permanent resident of the oral cavity. Extensive lesions of this infection can be painful and cause eating disorders and malnutrition, which is frequent in patients with AIDS [2-4].
Saliva plays an important role in maintaining oral health and prevents mouth candidiasis with two mechanisms. First, saliva is mixed with bacteria and debris, and by swallowing, these organisms are cleared from the oral cavity. Second, saliva contains anti-microbial proteins as lysozyme (muramidase) and lactoferrin, which are considered to regulate candida population in the oral cavity [5, 6]. It should be noted that lysozyme is an enzymatic protein that some of researchers have shown to be anti-fungal in the oral cavity [7, 8]. Lactoferrin is an iron-binding protein, which has proven in-vitro anti-fungal properties [9]. Changes in the host’s salivary flow rate and composition during HIV infection may alter the host’s defense mechanism that affects the candida’s adhesion and cloning. Therefore, the increase of oral candidiasis in HIV-positive patients may be related to defects in salivary defense proteins [10].
Numerous studies have examined the association of salivary proteins with oral candidiasis. In one study, Muller et al. showed that a decrease in salivary lactoferrin and IgA was associated with an increase in recurrent oral fungal infections in HIV-positive patients [11]. Even though some researchers have reported no significant association, other studies have shown a direct relation between these proteins and candidiasis [12-15]. Giving such inconsistent conclusions in this regard, the aim of this review study was to investigate the oral candidiasis relationship with salivary lysozyme and lactoferrin in patients with HIV infection. Knowing this connection can be useful in diagnosing and designing new treatment strategies for the prevention and treatment of fungal infections in these patients.

Material and methods

Search strategy

This systematic review was conducted based on the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement for reporting systematic reviews [16]. A focused question was produced according to the participants, intervention, control, and outcomes (PICO) principles [17]. The focused question for this review was “Is there an association between oral candidiasis and salivary lysozyme and lactoferrin in HIV-positive patients?” In this review study, all published articles with English abstract with the medical subject heading (MESH) terms and keywords of “Oral Candidiasis” or “Candida” and “Saliva” and “HIV” or “AIDS” and “Lysozyme” and “Lactoferrin” from Google Scholar, PubMed, Web of Science, Cochrane, and Scopus databases were searched from 1990 until April 2020. In the initial phase, the titles and abstracts of articles were reviewed by two independent individuals, based on inclusion and exclusion criteria. Disagreements were resolved with the third author’s discussion. Next, the full text of selected articles was reviewed. The quality of chosen studies was evaluated by the Newcastle-Ottawa scale method [18]. The data of selected articles were extracted using data extraction form. This form included the author’s name, year of publication, sample size, and the results of study.

Inclusion criteria

Inclusion criteria were the studies, in which levels of salivary lactoferrin or lysozyme in HIV-positive patients were assessed, and its association with oral candidiasis was evaluated.

Exclusion criteria

Reviews and case reports articles as well as in-vitro studies were excluded.

Results

During the initial search, 67 articles were obtained. Amongst 16 articles, after reviewing the abstracts, 13 appropriate articles were included in this study, based on the entry and exit criteria shown in Figure 1. In 11 studies, the relationship between salivary lactoferrin and oral candidiasis was investigated, 54% of which showed an increase in salivary lactoferrin in HIV-positive patients with candidiasis. In 37% of studies, no association between oral candidiasis and salivary lactoferrin in patients with HIV infection was indicated, and other studies revealed that oral candidiasis was associated with low levels of salivary lactoferrin in HIV-positive patients. Eight studies examined the relationship between salivary lysozyme and oral candidiasis, in which 63% showed no association, and 37% demonstrated an increase in salivary lysozyme in HIV-positive patients with candidiasis (Table 1).

Discussion

The results of this systematic review demonstrated that HIV-positive patients with higher candida counts had higher salivary lysozyme and lactoferrin, but the secretion of these salivary anti-microbial proteins was suppressed in HIV-positive patients, whose CD4+ cell counts were significantly lower. In patients with HIV infection, oral candidiasis is still known to be one of the most common opportunistic infections [2, 3]. There are a variety of defense systems against Candida albicans in the host body, including specific immune system and non-specific immune system. The innate immune system creates a defense barrier against infections [27]. Lactoferrin and salivary lysozyme play an important role in innate immunity. These salivary proteins are produced by the salivary glands, gingival crevicular fluid, and phagocytic cells [9]. When patients with HIV are divided into three groups based on CD4+ cell count, the lowest levels of these anti-microbial proteins are seen in the third stage; when CD4+ cells are less than 200, this indicate that the innate immunity is suppressed at this stage. 54% and 37% of the studies showed a direct relationship between lactoferrin and salivary lysozyme with oral candidiasis in patients with HIV infection, respectively, and the rest of the studies revealed no association or reverse relationship. Such an inconsistency of the results could be due to the collection of saliva at different stages of the disease, and different methods of its analyzing. According to studies, in the early stages of HIV infection, with a decrease in number of CD4+ cells, the innate immunity of saliva to compensation increases [28]. The accumulation of lymphocytes and granulocytes in response to candidiasis infections in the tissue produces cytokines and stimulates the production of salivary lysozyme and lactoferrin [13, 19]. On the other hand, the release of lactoferrin and lysozyme from cytoplasmic granules of macrophage and neutrophils also occurs [29]. However, increasing lactoferrin sometimes does not prevent candidiasis, which is probably due to the emergence of candidate species that have developed a resistance to lactoferrin and lysozyme, as HIV progresses. With a decrease in number of CD4+ cells below 200 μg/ml, the host immune system is unable to produce enough lactoferrin and lysozyme [21]. Significant reductions in lactoferrin and salivary lysozyme in the AIDS stage are likely due to reduced production of neutrophils and leukocytes. HIV infection reduces the number of leukocytes and decreases the movement of leukocytes into the oral mucosa affected by candidiasis infection. Decreasing CD4+ cells also weakens granulocytes activity, and reduces the release of granules containing immune components [28, 29].
The numerous anti-fungal mechanisms of lactoferrin cause this protein to be used in combination with anti-fungal agents. The use of lactoferrin in combination with fluconazole may be the most effective combination against Candida [30-32]. Our study has some limitations. Firstly, the sample size was limited for some groups, and secondly, our search was limited to English articles, which may consider language bias.

Conclusions

Understanding of various factors and conditions involved in candida cloning would be broadly related to increasing our understanding of fungal pathogenesis and host defense factors. The results of our study could be useful in diagnosing and designing new strategies for the prevention and treatment of fungal infections in HIV-positive patients. In addition to anti-fungal properties, non-toxicity to human cells could lead to lactoferrin being used in the future as a drug to prevent and treat fungal infections in patients with immunity difficulties.

Conflict of interest

The authors declare no conflict of interest with respect to the research, authorship, and/or publication of this article.

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