Oral manifestations of HIV infection in infants: a review article

EXPÓSITO-DELGADO AJ, VALLEJO-BOLAÑOS E, MARTOS-COBO EG. ORAL MANIFESTATIONS OF HIV INFECTION IN INFANTS: A REVIEW ARTICLE. MED ORAL PATOL ORAL CIR BUCAL 2004;9:410-20.

ABSTRACT

The vast majority of children with HIV infection present oral manifestations among the first signs of illness. These lesions are not produced directly by the virus, but are manifestations associated with HIV infection, and are not pathognomic of the infection itself. Some of these oral lesions have a prognostic value with regard to progression of the infection and the appearance of AIDS; independently of other, more commonly used markers. The essential risk factors that influence the development of such oral manifestations are the low number of CD4+ lymphocytes, xerostomia, and the lack of anti-retroviral therapy. Opportunist infections, such as mycoses - including pseudomembranous oral candidiasis, are found with higher frequency; followed by the herpetic viral infections. The oral lesions that appear in infected children differ in prevalence from those found in seropositive adults, some, such as parotid hypertrophy, present more exclusively in children, others, such as periodontal bacterial infections and Kaposi's Sarcoma, are lesions that predominate in the adult HIV-infected population. Given the current impact of the pandemic caused by HIV, it is the responsibility of dental professionals to prevent, detect, treat and control the oral lesions in those patients infected with HIV. All of which will be reflected in a reduction in transmission, lower mortality and greater long-term survival for infected children.

Key words: HIV infection, AIDS, oral candidiasis, parotid hypertrophy

INTRODUCTION

The Human Immunodeficiency Virus (HIV) was detected in children for the first time in 1982. Since then the infection has spread rapidly and is now an significant cause of death within the pediatric group (1). Although pediatric HIV infection presents many aspects in common with that of adults, the immunological immaturity of the child in the first months of life, and the difficulty of diagnosis in this period, confer on it some particular characteristics that differentiate it from that found in the adult population (3).

The HIV virus belongs to the lentivirus, a subfamily of the retrovirus. It consists of a single strand of RNA, characterised fundamentally by having a special tropism for cells with a CD4 surface receptor; although it also invades others without said molecule by way of its genetic variability, which enables it to form different strains in a single affected individual. The central fact is that the HIV elaborates different forms of evasion against the host response, and produces a progressive and irreversible deterioration in the immunological and nervous systems.

The transmission route in the paediatric population is principally the vertical, either before (intra uterine), during (intra partum) or after birth (through breast-feeding). However, the majority of infected children acquire the infection during birth, through exposure to infected blood and cervical vaginal secretions in the birth canal, where the HIV is found at high levels at the end of gestation and during birth. On the other hand, maternal breast-feeding is another important medium in developing countries.

Transmission through blood transfusions or blood derivatives is currently the cause of 3 to 6% of all paediatric cases of AIDS. Sexual transmission is not usual in the paediatric population, although some cases have been described due to sexual abuse. However, when talking of transmission in adolescence, this route is responsible for more than one third of cases in this age group. HIV titers are very low in saliva (<1 infectious particles/ml), and this form of transmission has never been described (2).

The diagnosis of initial infection in children is complicated when the transmission has been vertical. The seropositive mothers passively transmit the anti-HIV to the neonatal (by the vertical, intrauterine), and only one third of these children are infected. These antibodies decrease with time in those children who are not infected, in such a way that at 15 months 100 per cent will be seronegative. However, positive viral cultures have a definite diagnosis (3).

The initial HIV infection in children has no evident clinical consequences. The viral mass increases in a period of one to four months and following this time it is possible to detect HIV in the peripheral blood. In the first phases of infection, an activation of the B cells is produced (hypergammaglobulinemia >1750 g/L) with high levels of HIV antibodies, which can serve as a marker for the HIV infection in asymptomatic children. This increase is due to the loss of regulation of suppression by the CD8+ T cells. The decrease in CD4+ cells is less spectacular owing to the relative lymphocytosis normally present in breast-feeding children. Lymphopenia is infrequent in perinatal infection; it is usually observed only in older children and in those found to be in the final stages of the illness (2,3). When the level of CD4+ lymphocytes falls below 200 cells per mm3 then the patient is said to have AIDS. When the level falls below 100, the immune system is overcome and unable to fight the opportunist and on occasion mortal infections (2,4,5).

The system for classification of HIV used to establish the stage of the paediatric illness was created in Atlanta USA in 1987 by the Center for Disease Control and Prevention (CDC), proposing a classification based on fundamentally clinical criteria. In 1994 a revision of the previous classification was made, in that patients were included in mutually exclusive categories in accordance with three parameters: infectious stage, clinical stage and immunological stage. Category A (light symptoms) is made up of children who have at least two light symptoms, such as adenopathies, parotitis, hepatomegaly, splenomegaly, persistent or relapsing otitis media, sinusitis or dermatitis. In Category B (moderate symptoms) are those children with any of the following conditions: buccopharyngeal candidiasis persistent for more than two months, repetitive or chronic diarrhoea, persistent fever for more than one month, hepatitis, repetitive stomatitis caused by the herpes simplex virus, esophagitis or pneumonitis, disseminated chickenpox with visceral involvement, cardiomegaly or nephropathy. Category C (serious symptoms) or in other words AIDS, incorporates those children with two serious bacterial infections (sepsis, meningitis, pneumonia) in a period of two years, candidiasis of the esophagus or lower respiratory system, infection by herpes simplex virus causing mucocutaneous ulceration that persists for more than one month, Kaposi's sarcoma and cachexia (1-3).

The vast majority of children with HIV infection present oral manifestations among the first signs of illness. In addition, some of these oral lesions have a prognostic value regarding the progression of the infection and the appearance of AIDS, independently of the other most commonly used markers, such as the CD4+ cell count and the amount of virus in the plasma (1-6).

The prognosis for HIV infection in children varies according to diverse factors, such as the route of transmission, the age at which the infection was acquired, the presence of symptoms and the age at which the symptoms appear (3). An early diagnosis permits the rapid instigation of an anti-retroviral therapy, thanks to which the progression of the illness and the death rate at the beginning of infancy has notably decreased. Those children infected with HIV who receive treatment, live longer and have a better quality of life. In those breast-feeding infants with high viral mass and low CD4+ counts the illness tends to progress with great speed (2-4).

Given the current significance of the pandemic caused by HIV, it is the responsibility of dental professionals to prevent, diagnose as early as possible, treat and control the oral lesions in those patients infected with HIV. All of which will be reflected in a reduction in transmission, lower mortality and greater long-term survival for infected children (1-3,6,7).

MATERIALS AND METHODS

In order to carry out this study we have reviewed and compared studies from the majority of authors who have investigated oral manifestations of HIV infections in infants. Said manifestations have also been analysed in adults in order to contrast the results, and conclude that lesions caused by HIV in children are different entities in both clinical form and prevalence.

RESULTS AND DISCUSSION

The oral manifestations resulting from HIV infection are attributed to a decrease in CD4+ lymphocytes and to the severe compromise of the immune mediator cells, with both humoral and phagocytic dysfunction. No information exists as to whether the pathogenesis of HIV is in part responsible for these oral manifestations in children (5).

The majority of the investigations studied do not take into account, when talking about the prevalence of oral lesions, whether the children are receiving anti-retroviral treatment or not (8,9). Flanagan et al., in 2000, carried out a study to observe the prevalence of lesions in the soft tissues of children infected with HIV and receiving traditional anti-retroviral therapy (reverse transcriptase inhibitors) and either highly active or combined anti-retroviral therapy (protease inhibitors, reverse transcriptase inhibitors, and fixation and penetration inhibitors). It was concluded that with this last combined treatment there seems to be no significant oral implication in HIV-infected children, in contrast to reverse transcriptase inhibitor therapy or children who had not begun treatment. This fact creates an important bias when analyzing the presence or absence of oral lesions in different groups of children, as it does not take into account the use of anti-retroviral agents, or the time of diagnosis (8,9).

The types of oral lesions seen in HIV infection can be classified fundamentally into fungal, viral, bacterial, neoplastic and idiopathic.

Fungal manifestations:

Oral Candidiasis is the most frequently found mycosis in children infected with HIV. This opportunist-based infection has a prevalence that varies between 20 and 72% according to different authors; however, it remains the most common oral manifestation.

Only three clinical variants of oral candidiasis are currently recognised as being associated with HIV infection: pseudomembranous, erythmatous, and angular cheilitis. Hyperplastic candidiasis was eliminated from this classification in 1992 because of the difficulty that existed in defining it in these patients (10).

The pseudomembranous form is found most frequently in patients with advanced immunosuppression or full-blown AIDS. It presents in the oral cavity as lumps or clots, or white or yellowish cottony plaques semi-adhered and merging together, which become easily detached revealing an erythmatous mucosal and slightly bloody surface. The child has a burning sensation or disagreeable salty taste in the mouth. These lesions can appear at any site in the oral mucosa, being found most frequently on the tongue, soft and hard palate, and bucal mucosa (1,5,6,10).

The erythmatous form appears in the early phases of HIV infection, it is more difficult to diagnose and may therefore go unnoticed. It is found principally on either the side of the tongue, associated with papillary atrophy (rhomboidal glossitis) and even with some whitish stippling, or on the palate. A high percentage of cases present simultaneously according to Campo J. et al.

Angular cheilitis may or may not have an infectious origin. It is identified by the presence of erythmatous cracks and fissures in the oral commissures, accompanied by pain, stinging and burning.

The spreading of the mycotic infection must be prevented as soon as possible, not only to avoid its spread orally, but also towards the pharynx and esophagus, due to the fact that it changes taste and affects the intake of food (3,6). According to studies by Penelope J. et al., candidal esophagitis develops in about 20% of children, requires hospitalisation and intravenous therapy with amphotericin B.

In erythmatous candidiasis and angular cheilitis, local treatment with topical fungicides such as nystatin and miconazole (200,000 to 800,000 U) used 4 or 5 times a day is sufficient. In older children, oral nystatin (200,000 U) in tablets which dissolve slowly in the mouth and taken 5 times per day is preferable. In rebellious or chronic cases, and cases involving the pseudomembrane, adequate treatment consists of the oral administration of fluconazole or ketoconazole 6mg/kg of body weight for 5 to 7 days is sufficient, although it will be necessary to complete a long course of topical therapy. The advised therapy for HIV-infected children who have had two or more episodes of oral candidiasis, is either topical nystatin (100,000 Đ 400,000 U) twice a day or oral clotrimazole 10mg twice daily (5,6).

The appearance of oral candidiasis is an indicator of rapid progression towards the death of the patient; the average life expectancy is 3.4 years following its appearance (1,5).

The risk factors that influence the development of candidiasis are the low number of CD4+ lymphocytes and xerostomia. The frequent recurrences are due to either changes in biotype of the C. albicans, or the reduction in susceptibility to some of the anti-fungal agents (5,11). Studies by Diana M et al. in 1999 confirm the presence of a new type, C. dubliniensis, that appears almost exclusively in infantile HIV infection, however, a large gap in knowledge about its prevalence and pathogenesis remains; future investigations are necessary in order to clarify its role in infected paediatric patients (12).

The most recent investigations tend to predict candidal infection before it appears, to do this the composition of the saliva is studied. On the one hand the microbial commensal is obtained, and on the other the defensive agents, such as the immunoglobulins, hystatins, cystatins, prolines, proteins, and bacterial agents, such as lactoferrin and lysozyme, are obtained; this is based on the fact that a correlation between the hystatin levels and the presence of yeast-like forms in the oral cavity has been observed. In the results of this investigation, it is suggested that the mycoses may be influenced by the rate of saliva flow and by the secretion and concentration of hystatins at the level of the salivary glands (1,13,14).

Viral infections:

Within the most frequent oral viral infections in HIV seropositive children, we highlight those caused by the herpetic virus (Herpes Simplex virus type 1, Epstein-Barr virus, Cytomegalovirus and Varicella-Zoster virus).

The first infection by type 1 herpes simplex virus generates the primary herpetic gingivostomatosis, which is the most common viral infection. The acute phase is associated with variable degrees of fever and discomfort, cervical lymphoadenopathy, and intraoral and perioral lesions in the form of vesicles. These quickly break up leaving irregular (crater-like) ulcerous areas that become very painful. These ulcers heal within 10 to 14 days, except in children with severe HIV, where they can become chronic, converting into true membranes that may even require hospitalisation (1,3,6).

Lesions caused by herpes simplex in HIV-infected children usually appear in a recurrent and chronic form, able to progress rapidly towards mucocutaneous areas. The most frequent locations are the mucosa, lingual dorsum and hard palate (intraoral), lips and adjacent (perioral) cutaneous areas.

Its prevalence increases as the illness advances, and varies according to different authors, Kline (5) observed it in 24% of patients, Flaitz (13) in 6.4% while Santos et al. (9) found only 1.3%.

The diagnosis is based on the clinical picture, immunohistochemical analysis or culture (1).

The progression towards death when herpes simplex virus infection is present is an average of 4.3 years, so, when compared to oral candidiasis, the viral infection appears at more moderate stages of immunosuppression (5).

For the treatment of herpes simplex, the drug Acyclovir is used administered orally 10mg/kg 4 or 5 times per day. In severe lesions, or lesions which impede the intake of liquids, in doses of 10mg/kg intravenously every 8 hours can be used. Recurrences of these lesions are treated with prophylaxis of oral Acyclovir 10mg/kg 2 or 3 times per day (5).

The presence of Epstein-Barr virus in hairy leukoplakia has been demonstrated, and is also included in the risk group for children in cases of severe chronic immunosuppression. However, it is quite infrequent in comparison with the herpes simplex virus. Magalhaes et al. (15) speak of a prevalence of 2.63%, Flaitz et al. (16) agree on 2%. Other authors such as Costa et al. and Moniaci et al. did not observe hairy leukoplakia in the populations studied.

Hairy leukoplakia is an oral infection characterised by the appearance of a white fixed lesion, generally found on the edges of the tongue and having a corrugated or hairy surface. It is frequently colonised by candida. The lesion is completely asymptomatic and is associated with the progression to AIDS in only a few months (1,6). It requires treatment only when it aggravates the patient, the use of antifungals to prevent superinfection by candida is recommended. Oral acyclovir may produce remission in some cases, but recurrence is common following the interruption of the antiviral (5).

Herpes Zoster, caused by Varicella-Zoster, is another herpes virus that causes oral lesions in the form of ephemeral vesicles, which break up leaving ulcers. It is normally accompanied by characteristically distributed cutaneous lesions, which are frequently preceded by, and associated with, severe pain (3). These lesions present a low prevalence in HIV infected children, around 1% according to the findings of Flaitz et al. (16). Aguirre et al. affirm that the appearance of herpes zoster demonstrates a significant immunosuppression in these patients and usually has a poor prognosis in general (6).

The Cytomegalovirus (CMV) and the type 6 herpes virus, according to Kline, may be implicated in parotid hypertrophy, although its etiology remains unknown. Furthermore, they are responsible for large ulcers on the palate and pharynx which resemble large sores (5). Flaitz et al. (14) worked with a paediatric group in which only 3.2% of the HIV seropositive children had a history of cytomegalovirus infection, although the CMV were detected through viral culture techniques in at least 25% of the children included in the study, which implies that the CMV were incubating.

Bacterial infections

Within this group of infections, both gingivitis and periodontitis stand out. In HIV seropositive adults, periodontal infection is the most prevalent lesion, with a prevalence of 78.28% according to Ceballos et al. In children a lesser proportion, which varies according to the different studies, is found. Santos et al. found 17.5% in their sample, Moniaci et al. 3%, Murray et al. discriminate between a prevalence of 37% for gingivitis and 4.5% for periodontitis (18).

Gingivitis is observed in HIV-infected children during the eruption of both the deciduous and permanent teeth. It is characterized by a lineal band 2 to 3mm wide at the level of the marginal gingiva in the interproximal and vestibular margins, and is not a response to poor oral hygiene. It may appear in either a general or localised manner, the first of these being the most frequent. The gingival lesions do not rapidly progress to destructive periodontitis as occurs in HIV adults (3). As age increases (adolescence), so the periodontal lesions become similar to those found in adults.

Ulceronecrotizing gingivitis is characterized by the presence of gingival ulcerations, with necrosis which causes the destruction of the interdental papilla and gingival margins. This destruction may appear covered by fibrinous exudate. In developed countries, ulceronecrotizing gingivitis is rarely seen in children less than 10 years of age. However, in countries such as India and others in Africa where malnutrition and immunosuppression are closely linked, ulceronecrotizing gingivitis is one of the most common findings (1,6).

Ulceronecrotic periodontitis presents with necrosis of soft tissues and destruction of the bone and periodontal insertion. It is found more frequently in adolescents than in children, however, there are few authors who have described it in their studies (1).

As regards the presence of bacteria, according to the cytologic studies of saliva carried out by Flaitz et al. the Gram-negative organisms were the most common in subjects with a greater risk of suffering from gingivitis and periodontal disease (Prevotella spp., Fusobacterium spp., Veillonella spp. and Capnocytophaga spp.). The characterisation of these bacteria could have a predictive value for the development of gingivitis and periodontitis, but it is not yet clear if these micro organisms really appear in relation to HIV or not, only Lautropia mirabilis, of unknown potential pathogenesis, has been isolated in saliva samples from HIV seropositives (13). Actinobacillus actinomycetemcomitans appears notably in cases of periodontitis.

Many studies have not yet picked up these ulceronecrotizing lesions in infected children (15), although they have found early interproximal lesions. It is currently highly debated as to whether these periodontal alterations are conventional or non-specific to HIV/AIDS, because in population samples of infected children such as those of Leggott et al., periodontal involvement is associated with the presence of bacterial plaque, which reacts favourably to prophylactic dental treatment (3,5,9,17).

Other manifestations:

There are oral manifestations which present in HIV-positive children whose etiology we do not know. Some of these, such as parotid infection, are a more common finding in infected children than in the HIV seropositive adult population (3, 7).

At the initial stages of HIV infection, even without immunodepression, the parotid glands undergo an increase in size for no apparent medical cause, which provokes a perceptible facial disfiguration. This enlargement will be persistent or diffuse. In some children it disappears, in others it becomes persistent, even for longer than five years (3).

All the literature reviewed finds a prevalence of parotid hypertrophy that varies from the 8.8% of Santos et al. to 47% from Kline et al. In spite of this great disparity, all the authors recognise that the parotid involvement is more exclusive to the infected paediatric population (5,16,17). The etiology is uncertain, although studies undertaken by Viñals et al. have detected cytomegalovirus and type 6 human herpes virus in glandular tissue cultures, aside from other, still unconfirmed, auto-immune series (5,18). Other authors, such as Leggott, do not demonstrate evidence of said etiological agents, but do confirm the existence of a possible inflammatory origin for these lesions, due to the resolution of the process following steroid therapy (19).

Biopsies of salivary glands demonstrate a multifocal stratum or a diffuse lymphocytic infiltrate that consists predominantly of CD8 lymphocytes. In reality, they are cystic cavities covered in epithelium surrounded by lymphoid tissue, with the peculiarity that the glandular acini are not affected (20).

Glandular involvement can be indiscriminately unilateral or bilateral, and does not usually present with pain. According to Costa et al., it always appears associated with hepatomegaly, splenomegaly, and lymphoadenopathies. This manifestation is related to the slower progression of the disease caused by HIV. Patients with parotid hypertrophy are immunologically less compromised (higher percentages of CD4), and hence, the average survival in these patients from the appearance of the lesion is slightly longer at 5.4 years (1,9,21). This may mean a better prognosis for children infected with HIV when this manifestation is present.

Parotid hypertrophy may or may not be associated with xerostomia. Currently, no evidence exists on the relationship between the low rate of saliva flow and parotid involvement, it seems they are independent manifestations.

The prevalence of xerostomia oscillates, according to Hernández, between 10 and 13%, who furthermore indicates that it may be a side effect of the multiple anti-retroviral therapies, such as dideoxyinosine (DDI), to which the HIV-infected children are subjected, or to the monthly doses of gamma globulins that they receive. Xerostomia must be treated in order to alleviate the symptoms and prevent complications: rampant caries and oral candidiasis. The appropriate treatment, according to Kline, is to use saliva substitutes; sialagogues can be useful in some cases. There should be a strict control on the intake of sugar, and, more importantly, collutories or fluoride gel must be used to prevent dental caries. The use of stannous fluoride gel at 0.4% used in cuvette for five minutes daily is postulated as the standard in patients with a high risk of dental caries (1,5).

Kaposi's sarcoma is a malignant neoplasm of soft tissues, constituted by multifocal proliferation of small vessels, both blood and lymph, and their angioendothelial cells. The etiology is not clear and it is suspected that some oncogenic virus exists that infects the patients simultaneously with HIV (7). They usually appear in the hard palate or in any part of the oral mucosa. The symptomatology that presents is pain, dysphagia or aesthetic alteration (13) in 66% of those infected with HIV (1, 6, 7).

Its prevalence in the infant HIV+ population is very low, only isolated cases have been described, such as those of Hernández in 1998. The highest prevalence was found by Coulter in 1993, who described 25 cases of children with Kaposi's sarcoma in studies carried out in Uganda (1). In short, this lesion is not so relevant in infected children when compared to its prevalence in the adult population, which according to Ceballos et al. is 2.27% (1,5,22).

Recurrent oral sores appear in between 2 and 6% of the infected population (1). These lesions manifest as large necrotic areas in the oral mucosa (lips, soft palate and tongue), accompanied by intense pain. Superinfections can frequently appear. The influencing factors are stress, vitamin deficiency, trauma, immune dysfunction, viral infections, allergies and hormonal changes (1,5). Other non-specific ulcers arise and proliferate in the pharynx and palate, and do not follow the recognised pattern of recurrent aphthous stomatitis. They usually appear in acute periods of the illness, given the local and systemic alterations provoked by the HIV infection. Others are of iatrogenic origin caused by azidothymidine (AZT), interferon or neutropenia. The prevalence is of 0.25% and are therefore rarely seen, in accordance with the studies by Moniaci and Costa. This type of ulcer presents frequently in the rest of the non-infected pediatric population and its true significance in relation to its prevalence in HIV-infected patients is not yet clear (5).

Cervical adenopathies, along with pseudomembranous candidiasis, are some of the most common lesions (17). On physical examination they are some of the first symptoms found. Symmetrical or unilateral adenopathies usually present as regular, soft nodules, not adhered to any structure and which persist for many months (1,2).

With respect to dental caries, HIV infected children have a higher prevalence of caries than HIV seronegative children (1). Rampant caries are usually associated with xerostomia, since seropositive children produce less saliva than do healthy children, although this has the same buffer capacity in both cases (3).

The amount of caries increases with age and with the fall in level of CD4 (moderate or severe immunosuppression) (23). However, studies by López Pérez in 1999 did not obtain results which demonstrate that levels of caries in HIV seropositive children are related with the phase of the illness.

Costa et al., state in relation to dental caries, that they do not seem to be relevant in HIV patients since carious lesions are associated to factors such as poor oral hygiene, low socio-economic level, chronic treatment with drugs rich in sucrose (zidovudine), bottle feeding with sugared milk, living in communities without water fluoridization and frequent intake of carbohydrates. These phenomena could explain why Streptococcus mutans and Lactobacillus cultures obtained higher results in this group (1,17).

Further studies are needed to either confirm or deny these results (1,17,23).

CONCLUSIONS

The oral lesions that appear in children infected with HIV are not produced directly by the virus, one speaks of 'lesions associated with HIV', since they are not pathognomic of the infection.

The significance of these oral lesions lies in the fact that they are indicators of the immunological dysfunction, and hence are of prognostic value with respect to the progression of the illness. It is therefore necessary to integrate continuous and careful medical care of oral health as a part of the treatment for HIV infection in children. The prevention, diagnosis, treatment and control of these lesions is the job of the dental professional, who should therefore be informed about the relationship between the immunological markers and the appearance of oral lesions.

Nevertheless, a wide gap in knowledge still exists on the prevalence and history of these oral lesions in children, and therefore more investigations are required with the objective of confirming the association between the immunological and clinical categories.

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