DOI: 10.1111/ipd.12133
HIV-associated salivary gland disease – clinical or imaging diagnosis? INEˆS BEATRIZ DA SILVA RATH1, ANA PAULA C. A. BELTRAME2, AROLDO P. CARVALHO3, MARCELA B. SCHAEFFER4 & IZABEL C. S. ALMEIDA1 1
Department of Dentistry, Federal University of Santa Catarina, Florian opolis, Brazil, 2Federal University of Santa Catarina, 3 Florian opolis, Brazil, Department of Infectious Diseases, Joana de Gusm~ ao Hospital for Children, Florian opolis, Brazil, and 4 Clinic of Diagnostic Imaging, SONITEC, Florian opolis, Brazil
International Journal of Paediatric Dentistry 2015; 25: 233–238 Objectives. This work aimed at studying the sali-
vary gland disease (SGD) as it relates to associated factors, such as persistent generalised lymphadenopathy (PGL), lymphocytic interstitial pneumonia (LIP), clinical and immunological features of AIDS, and salivary flow rate and pH, as well as at exploring the relationship between the clinical diagnosis and the imaging diagnosis by ultrasound (US) examination of the parotid glands. Methods. Information regarding the observation of parotid gland enlargement, PGL, LIP, and clinical and immunological features of AIDS was gathered from medical records, and a saliva sample for
Introduction
HIV-associated salivary gland disease (HIV/ SGD) is an oral manifestation of HIV infection. It is asymptomatic and spontaneously resolves and recurs, being characterised by a diffuse soft-tissue oedema with unilateral or bilateral parotid gland involvement causing facial disfigurement1. It has a prevalence ranging from 11.5%2, 12.2%3, 19.6%4 to 25%5 in HIV-infected children. The parotid glands are enlarged as a result of an infiltration by (most probably) anti-HIV CD8 T-lymphocytes leading to the development of benign lymphoepithelial cysts that are occasionally associated with pain6. It may also be caused by a lymphoproliferation originating from the intraparotid lymph nodes7, or even by a prolonged inflammatory process which Correspondence to: A. P. C. A. Beltrame, Federal University of Santa Catarina, Prof. Walter de Bona Castelan 502, C orrego Grande, Florian opolis 88037-300, Brazil. E-mail: [email protected]
unstimulated salivary flow rate and pH measurement was collected from 142 children aged 3 through 10 years treated at the Department of Infectious Diseases of Joana de Gusm~ao Children’s Hospital, Florian opolis, SC, Brazil. High-resolution ultrasonography was performed in 58 children. Pearson’s chi-square test and t-test were used to evaluate the association between the variables. Results. A significant association was found between SGD and LIP. Ultrasound revealed a 50% higher incidence of SGD that was not reported in the patients’ records. Conclusion. US examination proved to be essential for the correct diagnosis and monitoring of the progression of HIV/SGD.
might have induced the proliferation of glandular epithelial cells within the lymph nodes8. In paediatric patients, HIV/SGD often occurs in conjunction with persistent generalised lymphadenopathy (PGL), which is a persistent or recurrent diffuse acute infection associated with pain and hyperthermia. In some children, it resolves spontaneously, while in others it may persist for long periods of time9. Another complication that may be related to this disorder is lymphocytic interstitial pneumonia (LIP), which is a clinical–pathological pattern of lung disease characterised by a diffuse interstitial infiltrate10. According to Michelow et al.11, salivary flow rate measurement, labial salivary gland biopsy, eye examination for keratoconjunctivitis detection and serological tests for antinuclear antibodies, rheumatoid factor and SS-A and SS-B antibodies can be used as an aid in the diagnosis of HIV/SGD. Furthermore, an incisional biopsy or fine-needle aspiration of the parotid glands may be needed to exclude the diagnosis of a tumour, such as a lymphoma or a Kaposi’s sarcoma.
© 2014 BSPD, IAPD and John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
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When examined by sonography, the affected glands showed an increase in size with typical characteristics of LIP and heterogeneous appearance, with multiple oval-shaped masses, being separated by thin septa, with no posterior shadowing12. Cystic images can be well visualised by ultrasound (US) examination, computed tomography or magnetic resonance imaging, given the high density of cystic fluids13. According to the literature, US examination and computed tomography scanning of the affected glands should be performed when clinical manifestations of HIV/SGD are observed12,14; however, it is important to note that, due to the recurrent nature and spontaneous remission of the disease, it is possible that at the time of the visit the increased volume is not clinically visible. This work aimed at studying the salivary gland disease (SGD) as it relates to associated factors, such as persistent generalised lymphadenopathy (PGL), lymphocytic interstitial pneumonia (LIP), clinical and immunological features of AIDS, and salivary flow rate and pH, as well as at exploring the relationship between the clinical diagnosis and the imaging diagnosis by ultrasound (US) examination of the parotid glands in HIV-infected children treated at the Department of Infectious Diseases of the Joana de Gusm~ ao Children’s Hospital (HIJG), Florian opolis, SC, Brazil. Materials and methods
This study was approved by the Human Research Ethics Committee of the Federal University of Santa Catarina (145/2001). Study population This was a cross-sectional study with HIVinfected children between the ages of 3 and 10 years treated in a day-hospital programme at the Department of Infectious Diseases of HIJG, a major referral centre in the state of Santa Catarina, Brazil, for the care of children with HIV infection or born to infected mothers. Of 150 children, a total of 142 subjects agreed to participate in the study, 64 (45%) males and 78 (55%) females, with a mean age of 6.6 years.
Data collection Each patient’s past medical history of HIV/ SGD, the dependent variable of the study, was obtained from their medical records, along with information about the presence of persistent generalised lymphadenopathy (PGL), lymphocytic interstitial pneumonia (LIP), and clinical and immunological features of HIV infection. The clinical features were described on the basis of the history of diseases and changes that each child had previously suffered from, according to the nomenclature used by the Brazilian Ministry of Health (2003), where ‘N’ is the asymptomatic category, ‘A’ stands for mild signs and/or symptoms, ‘B’ refers to moderate signs and/or symptoms and ‘C’ is the severe signs and/or symptoms15. The immunological features were based on the absolute count and percentage of CD4+ T-lymphocytes, according to the age recorded in the chart, resulting in a rating between 1 and 3: 1 = no suppression; 2 = moderate suppression; and 3 = severe suppression16. Saliva samples were collected for the analysis of the unstimulated whole-saliva flow rate and pH. The collection was performed with the subject seated in a dental chair, between 2 and 4 p.m., for a 5-min period, without stimulation, by moving the suction device gently and evenly around the buccal vestibule and floor of the mouth17. Immediately after the procedure, the unstimulated whole-saliva flow rate was calculated and the pH was determined using a portable digital pH meter (pHTester BNCTM; Oakton Instruments, Vernon Hills, IL, USA). High-resolution sonography (ATL 5000 Acoustic, ATL do Brasil) of the parotid glands was performed in 58 HIV-infected children. The examinations were carried out at a private diagnostic imaging centre by a medical radiologist. Data analysis Data were statistically analysed using Pearson’s chi-square test and t-test at a 5% significance level (SPSS 10.0.1; SPSS Inc. and SAS 8.02; SAS Systems Inc., IBM, Armonk, NY, USA).
© 2014 BSPD, IAPD and John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
HIV-associated salivary gland disease
Table 1. Association between HIV/SGD and PGL and LIP in polis, SC, Brazil. HIV-infected children. HIJG, Floriano History of PGL
History of LIP
History of HIV/SGD
Yes (%)
No (%)
Yes (%)
No (%)
Yes No Total
79 (55.63) 48 (33.81) 127 (89.44)
3 (2.11) 12 (8.45) 15 (10.56)
17 (11.97) 19 (7.04) 27 (19.01)
65 (45.77) 50 (35.22) 115 (80.99)
HIV/SGD, HIV-associated salivary gland disease; PGL, persistent generalised lymphadenopathy; LIP, lymphocytic interstitial pneumonia.
Results
Qf 142 children, 60 (42.25%) had no prior history of HIV/SGD and 82 (57.75%) did. The mean of unstimulated whole-saliva flow rate was 0.39 mL/min, with 80% of children whose means were within normal limits (ranging from 0.2 to 1.44 mL/min)18. 66.67% of children with an unstimulated whole-saliva flow rate below 2.0 mL/min had a history of HIV/SGD and 33.33% did not. The presence of a history of HIV/SGD was found to be associated with lower unstimulated whole-saliva flow rate with mean of 0.31 mL/min (0.34), but this difference was not statistically significant in comparison with children with no history of the disease (P = 0.505). The mean pH was 7.30 (ranging from 5.2 to 8.3). The presence of a history of HIV/SGD did not interfere with pH values, with a mean of 7.28 for children without prior history of HIV/SGD and 7.32 for children with prior history of HIV/ SGD (P = 0.712). A significant association was observed between HIV/SGD and LIP (P = 0.031), but there was no positive association between SGD and PGL (P = 0.184) (Table 1).
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No significant association was detected between HIV/SGD and the clinical (P = 0.074) and immunological features (P = 0.218) of AIDS. Regardless of the presence of HIV/SGD, the predominant symptom and suppression intensity was mild (Table 2). Among the 58 children whose parotid glands were examined by ultrasonography, 27 were males and 31 were females, with a mean age of 6.9 years. A normal sonographic appearance was observed in 39.66% of the children examined (Fig. 1a). Changes consistent with HIV/SGD were found bilaterally in 51.72% (n = 30) of them and unilaterally in 8.62% (n = 5) (Fig. 1b,c). And 67.64% of the children who had a previous history of HIV/ SGD showed changes in the parotid glands in the US examination. Among the children with no previous history, 50% also had a confirmed diagnosis of HIV/SGD when examined by ultrasound. Parotid glands with a normal sonographic appearance were found in 15.38% of children with a positive history of LIP. There was a positive association between HIV/SGD and PGL in 94.28% of subjects, as confirmed by the US examination. Moreover, 82.61% of children with a history of PGL exhibited glands with a normal sonographic appearance. Discussion
The prevalence of HIV/SGD in HIV-infected children in this study was 57.75%, being higher than in other studies in which the prevalence ranged from 11.5%2, 12 2%3, 19.6%4 to 25%5. It should be noted that in the works by Aguiar Ribeiro et al.2 and Fonseca et al.4 a smaller sample was used and that
polis, SC, Table 2. Distribution of HIV-infected children according to the clinical/immunological category. HIJG, Floriano Brazil. Clinical category Immunological category
N (%)
A (%)
B (%)
C (%)
1 2 3
5 (3.52) 1 (0.70) 0 (0.00)
14 (9.86) 21 (14.79) 11 (7.75)
19 (13.38) 19 (13.38) 17 (11.97)
6 (4.23) 15 (10.56) 14 (9.86)
Total (%)
6 (4.22)
46 (32.39)
55 (38.73)
35 (24.65)
Total (%) 44 (30.98) 56 (39.44) 42 (29.58) 142 (100)
N = asymptomatic; A = mild signs and/or symptoms; B = moderate signs and/or symptoms; C = severe signs and/or symptoms; 1 = no suppression; 2 = moderate suppression; 3 = severe suppression. © 2014 BSPD, IAPD and John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
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(a)
(b)
(c)
Fig. 1. Sonographic aspects of the parotid glands. (a) Parotid gland without any changes, the presence of extraparotid lymph nodes (arrows); (b) Parotid gland with slight changes, the presence of intraparotid lymph nodes (arrows) and lymphoproliferation originating from the extraparotid lymph nodes; (c) Parotid gland with severe changes, the presence of extraparotid lymph nodes (arrows) and diffuse lymphoproliferation originating from the intraparotid lymph nodes.
the study population in Chidzonga (2003)3 and Nabbanja et al.5’s studies included children and adults. A low unstimulated whole-saliva flow rate has been associated with HIV/SGD19,20. In this study, over 50% of the children with a history of HIV/SGD showed unstimulated whole-saliva flow rates lower than those of children with no history of the disease. Moreover, unstimulated whole-saliva flow rates below 2.0 mL/min were more prevalent in children who had a history of HIV/SGD than in those who did not. This finding is in agreement with the results of Flaitz et al.21, who observed a higher prevalence of hyposalivation (salivary flow below 0.1 mL/min) in HIV-infected children with parotid gland enlargement, compared with an uninfected control group. The US examination of the parotid glands showed that 67.65% of children with a history of parotid gland enlargement and 50% of children with no history showed changes in the parotid glands consistent with the diagnosis of HIV/SGD, corroborating the results of Goddart et al.12 and Kabenge et al.22. In the latter study, among the patients who had no previous enlargement, only 8% showed no changes in the parotid glands according to the sonographic findings. Among the patients who underwent examination of the parotid glands by ultrasound (n = 58), the data obtained from information from the medical records indicated a significant percentage of children with a positive history of HIV/SGD (60.34%). The results of the US examination, however, revealed that 32.35% of them did not show the typical features of this condition. It can be inferred that, in some cases, the parotid gland enlargement, regarded clinically as HIV/SGD, may have occurred as a result of other events, such as inflammatory or infectious processes23, lymphoproliferation originating from the intraparotid lymph nodes (Mandel & Hong, 1999), or total HIV/SGD remission9. It was possible to note in the literature review that research involving US examination and computed tomography scanning of the affected glands was carried out only when the clinical manifestations of HIV/SGD were present12,14; however, in view of the high
© 2014 BSPD, IAPD and John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
HIV-associated salivary gland disease
percentage found in our sample of ultrasound images consistent with the diagnosis of HIV/ SGD, in children both with and without a history of parotid gland enlargement, it can be assumed that this disease has a higher prevalence than that reported in the aforementioned studies, for it can occur in a subclinical form. Therefore, the diagnosis of HIV/ SGD based only on the clinical evidence of an increase in size of one or more salivary glands24 carries a high error rate, as seen in this study. This misdiagnosis can lead to no treatment of other inflammatory or infectious diseases, which could be a cause of morbidity in children with immunodeficiency. For this reason, it is suggested that the diagnosis of HIV/SGD be made based on imaging tests, which have greater specificity for the detection of this condition. Similarly, imaging examinations should be more frequently used also for monitoring the progression of HIV/ SGD, as patients with parotid lymphadenopathy may develop inflammatory or neoplastic lesions in these glands25. Lymphadenopathy of the salivary glands, especially the parotid glands, was also observed in patients with HIV/SGD26. In the present study, it was found that, among children with a history of enlargement and changes in the parotid glands consistent with HIV/SGD in the US examination, 95.65% presented with lymphadenopathy of the intra- and extraparotid lymph nodes and 100% of them had a history of PGL. Among those with no recorded history, 50% had the diagnosis confirmed by the US examination, of whom 83.33% had intra- and extraparotid lymphadenopathy and 100% a history of PGL. These data indicate that lymphadenopathy of the intra- and extraparotid lymph nodes accompanies HIV infection, forming part of the spectrum of lymphoproliferative disorders, such as PGL and HIV/SGD. Among children who showed glands with normal sonographic appearance, 82.61% (n = 19) had PGL. These results corroborate the observations made by Ioachim et al.27, who found that the lymph nodes of the salivary glands are a target for HIV infection (as is any other group of peripheral lymph nodes) and also that the histologic changes identified are
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similar to lesions that characterise PGL in HIV infection. Among the variables studied, a significant association was observed between HIV/SGD and the presence of lymphocytic interstitial pneumonia. The sonographic images revealed changes consistent with HIV/SGD in a large number of children with and without a history of parotid gland enlargement. US imaging examination is essential to accurately diagnosing and monitoring the progression of HIV/SGD and serves as an aid in the differential diagnosis from other conditions.
Why this paper is important to paediatric dentists ● Research about SGD is relevant, because this is a disease with significant prevalence in HIV-infected patients and often occurs even before other manifestations of AIDS. ● The sooner it is diagnosed, the better chance of implementing therapeutic measures that can positively affect the quality of life of the patient. ● The diagnosis by ultrasound has better specificity and can detect the disease even in a subclinical stage.
Conflict of interest
The authors declare no conflict of interest. References 1 Pinto A, Rossi SS. Salivary gland disease in pediatric HIV patients: an update. J Dent Child 2004; 71: 33–37. 2 Aguiar AR, Portela MB, Souza IPR. The oral health of HIV-infected Brazilian children. Int J Paediatr Dent 2013; 23: 359–365. 3 Chidzonga MM. HIV/AIDS orofacial lesions in 156 Zimbabwean patients at referral oral and maxillofacial surgical clinics. Oral Dis 2003; 9: 317–322. 4 Fonseca R, Cardoso AS, Pomarico I. Frequency of oral manifestations in children infected with human immunodeficiency virus. Quintessence Int 2000; 31: 419–422. 5 Nabbanja J, Gitta S, Peterson S, Rwenyonyi CM. Orofacial manifestations in HIV positive children attending Mildmay Clinic in Uganda. Odontology 2013; 101: 116–120. 6 Greenspan D, Greenspan JS. HIV-related oral disease. Lancet 1996; 348: 729–733. 7 Mandel L, Hong J. HIV-associated parotid lymphoepithelial cysts. J Am Dent Assoc 1999; 130: 528–532.
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8 Mandel L, Kim D, Uy C. Parotid gland swelling in HIV diffuse infiltrative CD8 lymphocytosis syndrome. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1998; 85: 565–568. 9 Leggott PJ. Oral manifestations of HIV infection in children. Oral Surg Oral Med Oral Pathol 1992; 73: 187–192. 10 Fishback N, Koss M. Update on lymphoid interstitial pneumonitis. Curr Opin Pulm Med 1996; 2: 429– 433. 11 Michelow P, Dezube BJ, Pantanowitz L. Fine needle aspiration of salivary gland masses in HIV-infected patients. Diagn Cytopathol 2012; 40: 684–690. 12 Goddart D, Francois A, Ninane J et al. Parotid gland abnormality found in children seropositive for the human immunodeficiency virus (HIV). Pediatr Radiol 1990; 20: 355–357. 13 Miller CR. Pediatric aspects of AIDS. Radiol Clin North Am 1997; 35: 1191–1221. 14 Rosso R, Pretolesi F, del Bono V et al. Benign lymphoepithelial parotid lesions in vertically HIVinfected patients. AIDS Patient Care STDS 2006; 20: 536–541. 15 Ministry of Health, Executive Secretariat National STD and AIDS. Guide Clinical Treatment of HIV Infection in Children from 2002 to 2003. Brasil: Ministry of Health, 2004. 16 Panel on Antiretroviral Therapy and Medical Management of HIV-Infected Children. Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection. http://aidsinfo.nih.gov/contentfiles/lvguidelines/pediatricguidelines.pdf [updated February 13, 2014]. 17 Navazesh M, Christensen CM. A comparison of whole mouth resting and stimulated salivary measurement procedures. J Dent Res 1982; 61: 1158– 1162.
18 Sreebny LM, Valdini A. Xerostomia. Part I: relationship to other oral symptoms and salivary gland hypofunction. Oral Surg Oral Med Oral Pathol 1988; 66: 451–458. 19 Grimoud AM, Arnaud C, Dellamonica P, Lodter JP. Salivary defence factor concentrations in relation to oral and general parameters in HIV positive patients. Eur J Oral Sci 1998; 106: 979–985. 20 Tenovuo J. Antimicrobial function of human saliva– how important is it for oral health? Acta Odontol Scand 1998; 56: 250–256. 21 Flaitz CM, Hicks MJ, Carter AB et al. Saliva collection technique for cytologic, microbiologic and viral evaluation in pediatric HIV infection. ASDC J Dent Child 1998; 65: 318–324. 22 Kabenge C, Ng S, Muyinda Z, Ameda F. Diagnostic ultrasound patterns of parotid glands in human immunodeficiency virus-positive patients in Mulago, Uganda. Dentomaxillofac Radiol 2010; 39: 389–399. 23 Schiødt M, Dodd CL, Greenspan D et al. Natural history of HIV-associated salivary gland disease. Oral Surg Oral Med Oral Pathol 1992; 74: 326–331. 24 Ramos-Gomez FJ, Hilton JF, Canchola AJ, Greenspan D, Greenspan JS, Maldonado YA. Risk factors for HIV-related orofacial soft-tissue manifestations in children. Pediatr Dent 1996; 18: 121–126. 25 Ellis GL. Lymphoid lesions of salivary glands: malignant and benign. Med Oral Patol Oral Cir Bucal 2007; 12: E479–E485. 26 Seifert G. Tumour-like lesions of the salivary glands. The new WHO classification. Pathol Res Pract 1992; 188: 836–846. 27 Ioachim HL, Ryan JR, Blaugrund SM. Salivary gland lymph nodes. The site of lymphadenopathies and lymphomas associated with human immunodeficiency virus infection. Arch Pathol Lab Med 1988; 112: 1224–1228.
© 2014 BSPD, IAPD and John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
HIV-associated salivary gland disease – clinical or imaging diagnosis? INEˆS BEATRIZ DA SILVA RATH1, ANA PAULA C. A. BELTRAME2, AROLDO P. CARVALHO3, MARCELA B. SCHAEFFER4 & IZABEL C. S. ALMEIDA1 1
Department of Dentistry, Federal University of Santa Catarina, Florian opolis, Brazil, 2Federal University of Santa Catarina, 3 Florian opolis, Brazil, Department of Infectious Diseases, Joana de Gusm~ ao Hospital for Children, Florian opolis, Brazil, and 4 Clinic of Diagnostic Imaging, SONITEC, Florian opolis, Brazil
International Journal of Paediatric Dentistry 2015; 25: 233–238 Objectives. This work aimed at studying the sali-
vary gland disease (SGD) as it relates to associated factors, such as persistent generalised lymphadenopathy (PGL), lymphocytic interstitial pneumonia (LIP), clinical and immunological features of AIDS, and salivary flow rate and pH, as well as at exploring the relationship between the clinical diagnosis and the imaging diagnosis by ultrasound (US) examination of the parotid glands. Methods. Information regarding the observation of parotid gland enlargement, PGL, LIP, and clinical and immunological features of AIDS was gathered from medical records, and a saliva sample for
Introduction
HIV-associated salivary gland disease (HIV/ SGD) is an oral manifestation of HIV infection. It is asymptomatic and spontaneously resolves and recurs, being characterised by a diffuse soft-tissue oedema with unilateral or bilateral parotid gland involvement causing facial disfigurement1. It has a prevalence ranging from 11.5%2, 12.2%3, 19.6%4 to 25%5 in HIV-infected children. The parotid glands are enlarged as a result of an infiltration by (most probably) anti-HIV CD8 T-lymphocytes leading to the development of benign lymphoepithelial cysts that are occasionally associated with pain6. It may also be caused by a lymphoproliferation originating from the intraparotid lymph nodes7, or even by a prolonged inflammatory process which Correspondence to: A. P. C. A. Beltrame, Federal University of Santa Catarina, Prof. Walter de Bona Castelan 502, C orrego Grande, Florian opolis 88037-300, Brazil. E-mail: [email protected]
unstimulated salivary flow rate and pH measurement was collected from 142 children aged 3 through 10 years treated at the Department of Infectious Diseases of Joana de Gusm~ao Children’s Hospital, Florian opolis, SC, Brazil. High-resolution ultrasonography was performed in 58 children. Pearson’s chi-square test and t-test were used to evaluate the association between the variables. Results. A significant association was found between SGD and LIP. Ultrasound revealed a 50% higher incidence of SGD that was not reported in the patients’ records. Conclusion. US examination proved to be essential for the correct diagnosis and monitoring of the progression of HIV/SGD.
might have induced the proliferation of glandular epithelial cells within the lymph nodes8. In paediatric patients, HIV/SGD often occurs in conjunction with persistent generalised lymphadenopathy (PGL), which is a persistent or recurrent diffuse acute infection associated with pain and hyperthermia. In some children, it resolves spontaneously, while in others it may persist for long periods of time9. Another complication that may be related to this disorder is lymphocytic interstitial pneumonia (LIP), which is a clinical–pathological pattern of lung disease characterised by a diffuse interstitial infiltrate10. According to Michelow et al.11, salivary flow rate measurement, labial salivary gland biopsy, eye examination for keratoconjunctivitis detection and serological tests for antinuclear antibodies, rheumatoid factor and SS-A and SS-B antibodies can be used as an aid in the diagnosis of HIV/SGD. Furthermore, an incisional biopsy or fine-needle aspiration of the parotid glands may be needed to exclude the diagnosis of a tumour, such as a lymphoma or a Kaposi’s sarcoma.
© 2014 BSPD, IAPD and John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
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When examined by sonography, the affected glands showed an increase in size with typical characteristics of LIP and heterogeneous appearance, with multiple oval-shaped masses, being separated by thin septa, with no posterior shadowing12. Cystic images can be well visualised by ultrasound (US) examination, computed tomography or magnetic resonance imaging, given the high density of cystic fluids13. According to the literature, US examination and computed tomography scanning of the affected glands should be performed when clinical manifestations of HIV/SGD are observed12,14; however, it is important to note that, due to the recurrent nature and spontaneous remission of the disease, it is possible that at the time of the visit the increased volume is not clinically visible. This work aimed at studying the salivary gland disease (SGD) as it relates to associated factors, such as persistent generalised lymphadenopathy (PGL), lymphocytic interstitial pneumonia (LIP), clinical and immunological features of AIDS, and salivary flow rate and pH, as well as at exploring the relationship between the clinical diagnosis and the imaging diagnosis by ultrasound (US) examination of the parotid glands in HIV-infected children treated at the Department of Infectious Diseases of the Joana de Gusm~ ao Children’s Hospital (HIJG), Florian opolis, SC, Brazil. Materials and methods
This study was approved by the Human Research Ethics Committee of the Federal University of Santa Catarina (145/2001). Study population This was a cross-sectional study with HIVinfected children between the ages of 3 and 10 years treated in a day-hospital programme at the Department of Infectious Diseases of HIJG, a major referral centre in the state of Santa Catarina, Brazil, for the care of children with HIV infection or born to infected mothers. Of 150 children, a total of 142 subjects agreed to participate in the study, 64 (45%) males and 78 (55%) females, with a mean age of 6.6 years.
Data collection Each patient’s past medical history of HIV/ SGD, the dependent variable of the study, was obtained from their medical records, along with information about the presence of persistent generalised lymphadenopathy (PGL), lymphocytic interstitial pneumonia (LIP), and clinical and immunological features of HIV infection. The clinical features were described on the basis of the history of diseases and changes that each child had previously suffered from, according to the nomenclature used by the Brazilian Ministry of Health (2003), where ‘N’ is the asymptomatic category, ‘A’ stands for mild signs and/or symptoms, ‘B’ refers to moderate signs and/or symptoms and ‘C’ is the severe signs and/or symptoms15. The immunological features were based on the absolute count and percentage of CD4+ T-lymphocytes, according to the age recorded in the chart, resulting in a rating between 1 and 3: 1 = no suppression; 2 = moderate suppression; and 3 = severe suppression16. Saliva samples were collected for the analysis of the unstimulated whole-saliva flow rate and pH. The collection was performed with the subject seated in a dental chair, between 2 and 4 p.m., for a 5-min period, without stimulation, by moving the suction device gently and evenly around the buccal vestibule and floor of the mouth17. Immediately after the procedure, the unstimulated whole-saliva flow rate was calculated and the pH was determined using a portable digital pH meter (pHTester BNCTM; Oakton Instruments, Vernon Hills, IL, USA). High-resolution sonography (ATL 5000 Acoustic, ATL do Brasil) of the parotid glands was performed in 58 HIV-infected children. The examinations were carried out at a private diagnostic imaging centre by a medical radiologist. Data analysis Data were statistically analysed using Pearson’s chi-square test and t-test at a 5% significance level (SPSS 10.0.1; SPSS Inc. and SAS 8.02; SAS Systems Inc., IBM, Armonk, NY, USA).
© 2014 BSPD, IAPD and John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
HIV-associated salivary gland disease
Table 1. Association between HIV/SGD and PGL and LIP in polis, SC, Brazil. HIV-infected children. HIJG, Floriano History of PGL
History of LIP
History of HIV/SGD
Yes (%)
No (%)
Yes (%)
No (%)
Yes No Total
79 (55.63) 48 (33.81) 127 (89.44)
3 (2.11) 12 (8.45) 15 (10.56)
17 (11.97) 19 (7.04) 27 (19.01)
65 (45.77) 50 (35.22) 115 (80.99)
HIV/SGD, HIV-associated salivary gland disease; PGL, persistent generalised lymphadenopathy; LIP, lymphocytic interstitial pneumonia.
Results
Qf 142 children, 60 (42.25%) had no prior history of HIV/SGD and 82 (57.75%) did. The mean of unstimulated whole-saliva flow rate was 0.39 mL/min, with 80% of children whose means were within normal limits (ranging from 0.2 to 1.44 mL/min)18. 66.67% of children with an unstimulated whole-saliva flow rate below 2.0 mL/min had a history of HIV/SGD and 33.33% did not. The presence of a history of HIV/SGD was found to be associated with lower unstimulated whole-saliva flow rate with mean of 0.31 mL/min (0.34), but this difference was not statistically significant in comparison with children with no history of the disease (P = 0.505). The mean pH was 7.30 (ranging from 5.2 to 8.3). The presence of a history of HIV/SGD did not interfere with pH values, with a mean of 7.28 for children without prior history of HIV/SGD and 7.32 for children with prior history of HIV/ SGD (P = 0.712). A significant association was observed between HIV/SGD and LIP (P = 0.031), but there was no positive association between SGD and PGL (P = 0.184) (Table 1).
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No significant association was detected between HIV/SGD and the clinical (P = 0.074) and immunological features (P = 0.218) of AIDS. Regardless of the presence of HIV/SGD, the predominant symptom and suppression intensity was mild (Table 2). Among the 58 children whose parotid glands were examined by ultrasonography, 27 were males and 31 were females, with a mean age of 6.9 years. A normal sonographic appearance was observed in 39.66% of the children examined (Fig. 1a). Changes consistent with HIV/SGD were found bilaterally in 51.72% (n = 30) of them and unilaterally in 8.62% (n = 5) (Fig. 1b,c). And 67.64% of the children who had a previous history of HIV/ SGD showed changes in the parotid glands in the US examination. Among the children with no previous history, 50% also had a confirmed diagnosis of HIV/SGD when examined by ultrasound. Parotid glands with a normal sonographic appearance were found in 15.38% of children with a positive history of LIP. There was a positive association between HIV/SGD and PGL in 94.28% of subjects, as confirmed by the US examination. Moreover, 82.61% of children with a history of PGL exhibited glands with a normal sonographic appearance. Discussion
The prevalence of HIV/SGD in HIV-infected children in this study was 57.75%, being higher than in other studies in which the prevalence ranged from 11.5%2, 12 2%3, 19.6%4 to 25%5. It should be noted that in the works by Aguiar Ribeiro et al.2 and Fonseca et al.4 a smaller sample was used and that
polis, SC, Table 2. Distribution of HIV-infected children according to the clinical/immunological category. HIJG, Floriano Brazil. Clinical category Immunological category
N (%)
A (%)
B (%)
C (%)
1 2 3
5 (3.52) 1 (0.70) 0 (0.00)
14 (9.86) 21 (14.79) 11 (7.75)
19 (13.38) 19 (13.38) 17 (11.97)
6 (4.23) 15 (10.56) 14 (9.86)
Total (%)
6 (4.22)
46 (32.39)
55 (38.73)
35 (24.65)
Total (%) 44 (30.98) 56 (39.44) 42 (29.58) 142 (100)
N = asymptomatic; A = mild signs and/or symptoms; B = moderate signs and/or symptoms; C = severe signs and/or symptoms; 1 = no suppression; 2 = moderate suppression; 3 = severe suppression. © 2014 BSPD, IAPD and John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
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(a)
(b)
(c)
Fig. 1. Sonographic aspects of the parotid glands. (a) Parotid gland without any changes, the presence of extraparotid lymph nodes (arrows); (b) Parotid gland with slight changes, the presence of intraparotid lymph nodes (arrows) and lymphoproliferation originating from the extraparotid lymph nodes; (c) Parotid gland with severe changes, the presence of extraparotid lymph nodes (arrows) and diffuse lymphoproliferation originating from the intraparotid lymph nodes.
the study population in Chidzonga (2003)3 and Nabbanja et al.5’s studies included children and adults. A low unstimulated whole-saliva flow rate has been associated with HIV/SGD19,20. In this study, over 50% of the children with a history of HIV/SGD showed unstimulated whole-saliva flow rates lower than those of children with no history of the disease. Moreover, unstimulated whole-saliva flow rates below 2.0 mL/min were more prevalent in children who had a history of HIV/SGD than in those who did not. This finding is in agreement with the results of Flaitz et al.21, who observed a higher prevalence of hyposalivation (salivary flow below 0.1 mL/min) in HIV-infected children with parotid gland enlargement, compared with an uninfected control group. The US examination of the parotid glands showed that 67.65% of children with a history of parotid gland enlargement and 50% of children with no history showed changes in the parotid glands consistent with the diagnosis of HIV/SGD, corroborating the results of Goddart et al.12 and Kabenge et al.22. In the latter study, among the patients who had no previous enlargement, only 8% showed no changes in the parotid glands according to the sonographic findings. Among the patients who underwent examination of the parotid glands by ultrasound (n = 58), the data obtained from information from the medical records indicated a significant percentage of children with a positive history of HIV/SGD (60.34%). The results of the US examination, however, revealed that 32.35% of them did not show the typical features of this condition. It can be inferred that, in some cases, the parotid gland enlargement, regarded clinically as HIV/SGD, may have occurred as a result of other events, such as inflammatory or infectious processes23, lymphoproliferation originating from the intraparotid lymph nodes (Mandel & Hong, 1999), or total HIV/SGD remission9. It was possible to note in the literature review that research involving US examination and computed tomography scanning of the affected glands was carried out only when the clinical manifestations of HIV/SGD were present12,14; however, in view of the high
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HIV-associated salivary gland disease
percentage found in our sample of ultrasound images consistent with the diagnosis of HIV/ SGD, in children both with and without a history of parotid gland enlargement, it can be assumed that this disease has a higher prevalence than that reported in the aforementioned studies, for it can occur in a subclinical form. Therefore, the diagnosis of HIV/ SGD based only on the clinical evidence of an increase in size of one or more salivary glands24 carries a high error rate, as seen in this study. This misdiagnosis can lead to no treatment of other inflammatory or infectious diseases, which could be a cause of morbidity in children with immunodeficiency. For this reason, it is suggested that the diagnosis of HIV/SGD be made based on imaging tests, which have greater specificity for the detection of this condition. Similarly, imaging examinations should be more frequently used also for monitoring the progression of HIV/ SGD, as patients with parotid lymphadenopathy may develop inflammatory or neoplastic lesions in these glands25. Lymphadenopathy of the salivary glands, especially the parotid glands, was also observed in patients with HIV/SGD26. In the present study, it was found that, among children with a history of enlargement and changes in the parotid glands consistent with HIV/SGD in the US examination, 95.65% presented with lymphadenopathy of the intra- and extraparotid lymph nodes and 100% of them had a history of PGL. Among those with no recorded history, 50% had the diagnosis confirmed by the US examination, of whom 83.33% had intra- and extraparotid lymphadenopathy and 100% a history of PGL. These data indicate that lymphadenopathy of the intra- and extraparotid lymph nodes accompanies HIV infection, forming part of the spectrum of lymphoproliferative disorders, such as PGL and HIV/SGD. Among children who showed glands with normal sonographic appearance, 82.61% (n = 19) had PGL. These results corroborate the observations made by Ioachim et al.27, who found that the lymph nodes of the salivary glands are a target for HIV infection (as is any other group of peripheral lymph nodes) and also that the histologic changes identified are
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similar to lesions that characterise PGL in HIV infection. Among the variables studied, a significant association was observed between HIV/SGD and the presence of lymphocytic interstitial pneumonia. The sonographic images revealed changes consistent with HIV/SGD in a large number of children with and without a history of parotid gland enlargement. US imaging examination is essential to accurately diagnosing and monitoring the progression of HIV/SGD and serves as an aid in the differential diagnosis from other conditions.
Why this paper is important to paediatric dentists ● Research about SGD is relevant, because this is a disease with significant prevalence in HIV-infected patients and often occurs even before other manifestations of AIDS. ● The sooner it is diagnosed, the better chance of implementing therapeutic measures that can positively affect the quality of life of the patient. ● The diagnosis by ultrasound has better specificity and can detect the disease even in a subclinical stage.
Conflict of interest
The authors declare no conflict of interest. References 1 Pinto A, Rossi SS. Salivary gland disease in pediatric HIV patients: an update. J Dent Child 2004; 71: 33–37. 2 Aguiar AR, Portela MB, Souza IPR. The oral health of HIV-infected Brazilian children. Int J Paediatr Dent 2013; 23: 359–365. 3 Chidzonga MM. HIV/AIDS orofacial lesions in 156 Zimbabwean patients at referral oral and maxillofacial surgical clinics. Oral Dis 2003; 9: 317–322. 4 Fonseca R, Cardoso AS, Pomarico I. Frequency of oral manifestations in children infected with human immunodeficiency virus. Quintessence Int 2000; 31: 419–422. 5 Nabbanja J, Gitta S, Peterson S, Rwenyonyi CM. Orofacial manifestations in HIV positive children attending Mildmay Clinic in Uganda. Odontology 2013; 101: 116–120. 6 Greenspan D, Greenspan JS. HIV-related oral disease. Lancet 1996; 348: 729–733. 7 Mandel L, Hong J. HIV-associated parotid lymphoepithelial cysts. J Am Dent Assoc 1999; 130: 528–532.
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