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Home , Herpes simplex, Sialadenitis

Rahayuningtyas/Setiadhi 37 AS A CAUSE OF

Etis Duhita Rahayuningtyas*, Riani Setiadhi**

Keywords: ABSTRACT Virus, Salivary gland , HIV, Background: Enlargement in the extraoral region with the absence of abnormal nonHIV dental and periodontal structures are sometimes seen in dental practice, sometimes followed by . Enlargement of the acute nonsuppurative salivary glands has been associated with several types of . The purpose of this paper is to review salivary gland diseases associated with non-HIV and HIV viral . Discussion: Non-HIV viruses which were detected in the salivary glands including Paramyxovirus, (CMV), virus (HCV), human papilloma viruses (HPV), Epstein-Barr virus (EBV), human virus (HHSV-8), and coxsackie virus. HIV-associated typically presents with xerostomia and/or intraglandular lymph nodes, and diffuse infiltrative lymphocytosis syndrome (DILS). The most common viral conditions in salivary gland disorders are and HIV. Enlargement and of the glandular structures will affects the control of salivary secretion by nerves. Parasympathetic nerves block conducted signals to the salivary glands, so the salivary flow is decreased. Conclusion: There is association between viral infection and diseases of the salivary gland. By knowing sequelae viruses on the salivary gland, dentists are expected to understand the clinical condition and therapeutic that should be given to the patients.

INTRODUCTION (CMV), hepatitis C virus (HCV), Human Pap- illoma Virus (HPV), Epstein-Barr Virus (EBV), Saliva is a complex combination of fluids, Human Herpes Virus 8 (HHV-8) and HIV. 4,9–15 electrolytes, enzymes, and macromolecules Other virus detected in Saliva are coxsackie vi- that together do several important functions: rus, influenza, parainfluenza virus, echovirus, lubrication to help swallowing; producing am- BK virus, Human T-lymphotropic virus (HTLV), ylase enzymes to help digestion; taste mod- (HHV-6), human herpes- ulation; protection against caries and patho- virus 7 (HHV-7), Kaposi sarcoma virus (KSHV), gens.1–3 The salivary glands are the paired guinea pig CMV, mouse CMV (MCMV), mouse parotid, submandibular and lingual glands polyomavirus (PyV), encephalomyocarditis along with several hundred minor salivary (EMC).6,9 Sometimes accompanied with xero- glands, distributed through the upper aerodi- stomia as the manifestation of viral infection. gestive system.1,4,5 HIV-associated salivary gland disease typi- Salivary gland disorders are often associ- cally presents with xerostomia and/or swelling ated with viral infections.1,4,6–8 Enlargement of of the major salivary glands. It encompasses the acute nonsuppurative salivary glands has multitude of conditions like lymphoepithelial le- been associated with several types of virus- sions, cysts involving the salivary gland tissue es.4,7 Viruses that cause most gland enlarge- and/or intraglandular lymph nodes, Sjogren’s ment are paramyxovirus, cytomegalovirus syndrome-like conditions, diffuse infiltrative

* Specialist Programme, Faculty of Dentistry, Universitas Padjadjaran, Bandung. **Lecturer Oral Medi- cine Department, Faculty of Dentistry, Universitas Padjadjaran, Bandung Korespondensi: [email protected]

ODONTO Dental Journal. Volume 6. Special Issue 1. April 2019 38 VIRUS AS A CAUSE OF SALIVARY GLAND DISEASES lymphocytis syndrome (DILS), and other re- Non-HIV Viral Infection of The Salivary ported lesions of the major salivary glands.16–19 Gland About 5% of HIV patients exhibit HIV-Associat- Paramyxovirus/Mumps ed salivary gland disease (HIV-SGD).8 Mumps is an acute, self-limiting, contagious In this literature study, we dividing viral in- viral infection characterized chiefly by unilateral fections salivary gland disease due to non-HIV or bilateral swelling of the parotid, although all and HIV. The purpose of this paper is to review salivary glands may be involved.8,9 85% of cas- salivary gland diseases associated with non- es occur in children younger than 15 years.1,9 HIV and HIV viral infections. Human are the only natural host. Infection occurs following exposure through the upper LITERATURE REVIEW respiratory tract by droplet, aerosol, direct con- tact, or fomites. The prodromal symptoms are Viruses in Latin means venom or poison. , malaise, and headache. Approximately Viruses are ultramicroscopic organisms which 24 hours later, glandular swelling, tenderness, breed in living cells, inert metabolically, capa- and associated earache can occurs. Resolu- ble of infecting other organisms. The size of tion of symptoms generally occur in 10 days.9 viruses ranges from 10 millimeters or less to Complications including orchitis, acute pan- more than 200 millimicrons. The virus consists creatitis, meningoencephalitis, deafness, and of a DNA or RNA nucleus, surrounded by a mastoiditis.8,9 capsid made of protein or an outer envelope Mumps should be differentiated from other made of glycoproteins and lipids derived from parotid swelling which were caused by influen- the host cell membranes.8,9,11,13,14 za, parainfluenza 1 and 3, coxsackie, HIV, cy- Classification of diseases caused by vi- tomegalovirus, Sjögren’s syndrome, pleomor- ruses is difficult because of the virus size and phic adenoma, etc.8 Diagnosis is confirmed metabolic system that have not been fully un- through viral test. The treatment are derstood. International Committee on Nomen- supportive measures, including hydration, rest, clature of Viruses of the International Associa- oral hygiene instruction and pain control or an- tion of Microbiological Societies has classified tipyretic.4,9 According to Centers for Disease them into groups according to the type of nu- Control and Prevention (2014), vaccination is cleic acid, the size, shape, and substructure of 88% effective in preventing mumps and has the particle.8 reduced the incidence by 99%.1 Currently, the Paramyxovirus, cytomegalovirus (CMV), CDC recommends mumps patients should hepatitis C virus (HCV), Human Papilloma Vi- avoid contact with others from the time of di- rus (HPV), Epstein-Barr Virus (EBV), Human agnosis until at least five days after the onset Herpes Virus 8 (HHV-8) and HIV are several of by staying at home from work or viruses that causing salivary gland enlarge- school and in a separate room if possible.4,23 ment and sometimes xerostomia. 4,9–15 In this Cytomegalovirus (CMV) paper we will review those viruses, divided into CMV (HHV-5) is a member of the Herpes- non-HIV viral infections of the salivary gland viridae family. As the characteristic of other and HIV associated salivary gland disease. members of , CMV can become latent after initial exposure and infection and

ODONTO Dental Journal. Volume 6. Special Issue 1. April 2019 Rahayuningtyas/Setiadhi 39 may become reactivated when favorable con- be in the form of ganciclovir, valganciclovir, ditions are present. The majority of CMV infec- , or cidofovir.4,24 tions are , especially in healthy Hepatitis C Virus (HCV) individuals; however, in immunocompromised Hepatitis C virus (HCV) is one of the ma- patients and neonates, the infection can be jor causes of chronic liver disease worldwide, life-threatening. In the young adult, acute CMV as the global estimated prevalence of HCV infection presents with fever, malaise, ; is 2.2% with 40-75% of patients with chronic and lymphadenopathy. Oral and HCV infection exhibit at least one clinical ex- maxillofacial manifestations of CMV in immu- trahepatic manifestation (EHM).15,20 HCV infec- nosuppressed patients typically present as tion has many extrahepatic manifestations, in- persistent oral ulcerations and major salivary cluding and chronic major salivary gland infections, with or without concomitant gland enlargement and complaints of xerosto- alterations in salivary flow.4,24 CMV infection mia and sicca syndrome (Sjogren-like sialade- has been investigated as one of the causative nitis) are common.4,20,27 agents in Sjogren’s syndrome with a molecular The diagnosis of HCV infection is estab- mimicry mechanism of pathogenesis. Viruses lished by the serologic detection of anti-HCV affect exocrine tissue primarily through plas- by ELISA and HCV DNA by PCR. macytoid dendritic cells (pDCs) and Toll-like-re- Treatment of patients with acute HCV infection ceptors (TLRs).25 occurs through receives weekly PegIFN-alpha or standard in- blood transfusion, allograft transplants, sexual terferon. Hepatitis-associated sialadenitis and contact, fomites, urine, saliva, and respiratory xerostomia are treated symptomatically.4 secretions.4,24,26 In HIV-positive patients, the Human Papilloma Virus (HPV) degree of CMV-induced sialadenitis and/or xe- Human Papilloma Virus (HPV) has been rostomia was found to be proportional to the vi- demonstrated to be the trigger of neoplastic ral load and inversely proportional to the CD4+ diseases of the head and neck.10,28 Moreover, cell count. the medical literature provides only little evi- Several diagnostic modalities for CMV are dence about the role of HPV in salivary gland available including serology, qualitative and tumors.13,29 HPV-16 and HPV-18 are the most quantitative PCR, as well as histopathology. commonly detected high-risk types.28,30,31 Due The choice of test is based on the status of to the growing rates of salivary gland tumors the of the patient. Treatment and positivity of HPV types 16 and 18, some in those with symptomatic infection are sup- studies hypothesized that use of the two avail- portive and symptomatic care (i.e., , able HPV for carcinoma may rest, hydration). Immunocompromised patients cause a reduction of salivary gland .29–32 require aggressive antiviral therapy that may

Table 1. Differences between sialadenitis in Sjogren’s syndrome and hepatitis C virus. Modified from Carrozzo M et al.15

ODONTO Dental Journal. Volume 6. Special Issue 1. April 2019 40 VIRUS AS A CAUSE OF SALIVARY GLAND DISEASES Epstein-Barr Virus (EBV) HIV infection and has increased in the adult Same like HPV, studies in head and neck HIV population.6,16 Typically, HIV-SGD pres- revealed that Epstein-Barr virus ents a unilateral or bilateral diffuse soft swell- (EBV) have implicated as aetiological factors.11 ing resulting in facial disfigurement, and may EBV is an enveloped DNA herpesvirus that is be associated with pain.6 As HIV progresses, transmitted by saliva and is shed even in ap- salivary glands are infiltrated with CD8 lym- parently healthy subjects. EBV not only found phocytes leading to diffuse infiltrative lympho- in malignant neoplasms like salivary gland cytosis syndrome, resulting in salivary gland , but also in benign lesions such as enlargement. lymphoepithelial cyst and Warthin’s tumor.11,33 Another manifestation of HIV-associated Some studies have been founded that EBV is salivary gland disease is that qualitative and the co-factor in the development of Sjogren’s quantitative xerostomia (reduced salivary se- syndrome.25 cretion) may occur. The causes of xerostomia Human Herpes Virus 8 (HHV-8) including drugs (antiretrovirals, antifungals, Human Herpes Virus 8 (HHV-8), a gam- chemotherapeutics, antihistaminics, mood-al- ma-2 herpes virus (rhadinovirus) which nat- tering drugs, multivitamins), oral diseases urally infects only humans, is the cause of () or as a part of the progression several neoplastic disorders among immuno- of the HIV disease.8,17 There are evidence compromised individuals, especially Kaposi’s that HIV-SGD increases with HAART therapy.6 sarcoma, although salivary gland Kaposi’s sar- The dentist should identify xerostomia early coma is rare. Dalpa et al, 2007 investigate that and provide nutritional counseling as well as HHV-8 infection could play a role in a subset of preventive treatment with fluorides and other adenoid salivary neoplasms.9,12 agents including chlorhexidine/benzydamine Coxsackie Virus hydrochloride and triclosan/fluoride mouth Coxsackie virus is an RNA virus potential rinse.18 Management of HIV associated xero- localized, presence and replicates in exocrine stomia involving antiretroviral therapy, oral hy- glands of patients with Sjogren’s syndrome. giene instruction, and sialagogues.1 Triantafyllopou et al, 2004, reported for the first Diffuse Infiltrative Lymphocytic Syndrome time an association of a infec- (DILS) tion with primary Sjogren’s syndrome. Cox- DILS is characterized by salivary and lac- sackie virus replication takes place in the sub- rimal glandular swelling and sicca symptoms mucosal lymph tissue and then disseminates of various degrees of intensity, accompanied to the reticuloendothelial system. Further dis- by a proliferation of CD8+ lymphocytes and semination targeting the organs occurs follow- lymphocytic infiltration of the various organ ing a second viremia. RNA from two strains, including parotid glands, lacrimal glands, CVB4 and CVA13,has been identified in minor kidneys, muscles, nerves, lungs, and lymph salivary gland samples from pSS, therefore im- nodes in association with HIV infection.6,16 plicating Coxsackie virus of a potential environ- DILS mimicking Sjogren’s syndrome in terms mental trigger for Sjogren’s syndrome.25,34–36 of sicca symptoms, salivary glandular enlarge- HIV-Associated Salivary Gland Disease ment, histology, and predisposition to develop (HIV-SGD) non-Hodgkin’s lymphoma.6 HIV-SGD is define as AIDS in pediatric ODONTO Dental Journal. Volume 6. Special Issue 1. April 2019 Rahayuningtyas/Setiadhi 41 Table 2. Comparison of Salivary Gland Disorders: HIV-associated Salivary Gland Disease vs Sjogren’s Syndrome6

DISCUSSION ruses have been detected within the salivary glands of Sjogren’s syndrome patients i.e. The viral organism that first comes to mind hepatitis C virus (HCV) and Coxsackie virus, when considering non-HIV viral infections of both of which require more investigation be- the salivary glands is the mumps virus. The fore they are classified as being the etiologi- mumps virus is a paramyxovirus from influen- cal agent of Sjogren’s syndrome.20,25,34–36 The za and Newcastle groups. Like , it is diagnosis can be confirmed by viral serology a single-stranded RNA virus. Humans are the examination. only natural host.9 Some systemic complica- The epidemiology of HIV-SGD strongly tions may be serious, including meningitis, en- suggests the involvement of a viral opportun- cephalitis, hepatitis, carditis, orchitis and hear- ist in its pathogenesis.16 The conditions that ing loss, therefore the patient must be isolated associated with HIV including xerostomia, for several days.4,7 has been reported DILS, lymphoepithelial lesions of the parotid eradicated outbreaks.9 The treatment are sup- gland, CMV infection, hepatitis C virus infec- portive care. tion, mumps, sialodenosis, parotid cysts.4,8,16,17 Several viruses, including DNA, RNA, and Another significant increase in prevalence of retroviruses have been considered as the HIV-SGD was reported in patients under high- important co-factors in the development of ly active antiretroviral therapy (HAART) in the Sjogren’s syndrome. The two DNA viruses that AIDS population.19 The relationship between have been studied in association with Sjogren’s HAART and HIV-SGD may be due to the pa- syndrome are cytomegalovirus (CMV) and Ep- tients in early stages of the disease who re- stein-Barr virus (EBV).25,36,37 Overall the data main in the initial phase of HAART therapy and regarding CMV and EBV as causative agents still have relatively high viral loads and are thus for Sjogren’s syndrome are contradictory, and, subject to an increased risk of developing HIV- because Sjogren’s syndrome does not occur SGD.16,19 in most cases of viral infection in vivo. The link The most common viral infection conditions between reactivation and induc- in salivary gland disorders are mumps or HIV tion remains to be established. Epstein Barr with swelling as the clinical presentation, often virus (EBV), human papillomavirus (HPV), bilateral; may be tender, followed by xerosto- human herpesvirus-8 (HHV-8) have an asso- mia. Xerostomia is defined as the subjective ciation with tumorigenesis and lead into some sensation of oral dryness that may or may not in salivary gland.11–13,33 Two RNA vi- be associated with a reduction in salivary out-

ODONTO Dental Journal. Volume 6. Special Issue 1. April 2019 42 VIRUS AS A CAUSE OF SALIVARY GLAND DISEASES put. Xerostomia may be transient, prolonged or temp Dent Pract. 2008;9(3):072-080. 4. Glick M. Burket’s Oral Medicine. 12th ed. Shel- permanent depending upon the duration of the ton, Connecticut: People’s Medical Publishing condition. Acute viral infection is the temporary -USA; 2015. 5. Tucker, A.S, Miletich I, ed. Salivary Glands De- cause of xerostomia, meanwhile, Sjogren’s velopment, Adaptation, and Disease. Vol 14. syndrome and tumor that precipitated by vi- London: Frontiers of Oral Biology; 2010. 37–39 6. Jeffers L. Viruses and Salivary Gland Disease ( ral infection, are the permanent cause. SGD ): Lessons from HIV SGD. 2011:79-83. Salivary gland cells are intimately associated 7. Bradley P, O’Hara J. Diseases of the salivary with the autonomic nervous system. Parasym- glands. . 2015;33(12):614-619. 8. Shafer, Hine, Levy. Shafer’s Textbook of Oral Pa- pathetic and sympathetic nerves run together thology. 7th ed. (Rajendran R, Sivapathasunda- with Schwann cells to the target cells in sali- ram B, eds.). Elsevier; 2012 9. Schreiber A, Hershman G. Non - HIV Viral In- vary glands. Parasympathetic stimulates sali- fections of the Salivar y Glands. Oral Maxillofac va, and sympathetic is inhibiting saliva produc- Surg Clin NA. 2009;21(3):331-338. doi:10.1016/j. coms.2009.04.003. tion. Parasympathetic and sympathetic nerves 10. Hühns M, Simm G, Erbersdobler A, Zimpfer A. are in contact with many types of cell in sali- HPV Infection , but Not EBV or HHV-8 Infec- tion, Is Associated with Salivary Gland Tumours. vary glands, including acinar, ductal and myo- Biomed Res Int. 2015;2015(Nov.):10-17. epithelial cells as well as blood vessels.40,41 11. Lin FC, Chen P, Tsao T, Li C, Jeng K, Tsai SC. Prevalence of human papillomavirus and Ep- Enlargement and inflammation of the glandu- stein – Barr virus in salivary gland diseas- lar structures will affect the control of salivary es. J Int Med Res. 2014;42(5):1093-1101. doi:10.1177/0300060514543041. secretion by nerves. Parasympathetic nerves 12. Dalpa E, Gourvas V, Baritaki S, et al. High prev- block conducted signals to the salivary glands, alence of Human Herpes Virus 8 (HHV-8) in patients with Warthin ’ s tumors of the salivary therefore the salivary flow is decreased. gland. J Cilnical Virol. 2018;42(2008):182-185. 13. Hafed L, Farag H, Shaker O, El-rouby D. Is hu- man papilloma virus associated with salivary CONCLUSION gland neoplasms ? An in situ-hybridization study. Arch Oral Biol. 2012;57(9):1194-1199. 14. Alavian SM, Mahboobi N, Mahboobi N, Karay- There is association between viral infection iannis P. Oral Conditions Associated with Hep- and diseases of the salivary gland. In general, atitis C Virus Infection. Saudi J Gastroenterol. 2013;19(6):245-252. viral infection of the salivary gland may result 15. Carrozzo M, Scally K. Oral manifestations of in swelling and/or reduced saliva production. hepatitis C virus infection. World J Gastroenterol. 2014;20(24):7534-7543. By knowing sequelae viruses on the salivary 16. Islam NM, Bhattacharyya I, Cohen DM. Salivary gland, dentists are expected to understand the gland pathology in HIV patients. Diagnostic His- topathol. 2012;18(9):366-372. clinical and therapeutic conditions given to pa- 17. Nittayananta W, Chanowanna N, Jealae S, tients. Nauntofte B, Stoltze K. Hyposalivation , xero- stomia and oral health status of HIV-infected subjects in Thailand before HAART era. J Oral REFERENCES Pathol Madicine. 2010;39:28-34. 18. Patel M, Ph D, Shackleton J, et al. Antifungal Ef- fect of Mouth Rinses on Oral Candida Counts and 1. Wilson KF, Meier JD, Ward PD. Salivary Gland Salivary Flow in Treatment-Naïve HIV-Infected Disorders. Am Fam Physician. 2018;89(11):882- Patients. AIDS Patient Care STDS. 2008;22(8). 888. 19. Patton LL. Current Strategies for Prevention of 2. Malathi N, Mythili S, Vasanthi HR. Salivary Diag- Oral Manifestations of HIV. Oral Surg Oral Med nostics : A Brief Review. ISRN Dent.2014;29(1):1- Oral Pathol Oral Radiol. 2016;121(1):29-38. 10. 20. Carrozzo M. Oral diseases associated with 3. De Almeida PDV, Grégio AMT, Machado MÂN, hepatitis C virus infection . Part 1 : sialadeni- De Lima AAS, Azevedo LR. Saliva composition tis and salivary glands lymphoma. Oral Dis. and functions: A comprehensive review. J Con- 2008;14(2):123-130.

ODONTO Dental Journal. Volume 6. Special Issue 1. April 2019 Rahayuningtyas/Setiadhi 43 21. Liao H, Gu Y, Diaz A, et al. Use of the CRISPR/ EBV-associated B-cell lymphoproliferative disor- Cas9 system as an intracellular defense against ders of the minor salivary gland : a case report. HIV-1 infection in human cells. Nat Commun. Oral Maxillofac Surg Cases. 2016;2(3):27-30. 2015;10:6(March):1-10. 34. Voulgarelis M, Tzioufas AG. Pathogenetic mech- 22. Advisory G, Blood C, Blut A, Assessment S. Hu- anisms in the initiation and perpetuation of man Immunodeficiency Virus ( HIV ). Transfusin Sjogren’s syndrome. Nat Publ Gr. 2010;6(9):529- Med Hemotherapy. 2016;43(May):203-222. 537. 23. Mumps _ For Healthcare Providers _ CDC. 35. Sarkar PK, Patel N, Furie RA, Talwar A. Pul- https://www.cdc.gov/mumps/hcp.html. Published monary manifestations of primary Sjogren’s 2018. Accessed September 20, 2018. syndrome. Indian J Chest Dis Allied Sci. 24. Silva D, Medeiros R. Pathogenesis, Diagnosis 2015;51(May):93-101. and Therapeutics in Human Cytomegalovirus In- 36. Emamian ES, Leon JM, Lessard CJ, et al. Periph- fection. J Infect Dis. 2017;5(2):37-39. eral blood gene expression profiling in Sjogren’s 25. Igoe A, Scofield RH. Autoimmunity and infection syndrome. Genes Immun. 2009;10:285-296. in Sjogren’s syndrome. Curr Opin Rheumatol. 37. Tzioufas AG, Kapsogeorgou EK, Moutsopoulos 2013;25(4):480-487. HM. Pathogenesis of Sjögren’s syndrome : What 26. Bate SL, Dollard SC, Cannon MJ. Cytomegalo- we know and what we should learn. J Autoim- virus Seroprevalence in the : The mun. 2012;39(1-2):4-8. National Health and Nutrition Examination. Clin 38. Krishnamurthy S, Vasudeva SB, Vijayasarathy Infect Dis. 2010;30345(11):1439-1447. S. Salivary gland disorders: A comprehensive re- 27. Jacobson IRAM, Cacoub P, Maso LDAL, Harri- view. World J Stomatol. 2015;4(2):56-71. son SA, Younossi ZM. Manifestations of Chron- 39. Napeñas JJ, Brennan MT, Fox PC. Diagno- ic Hepatitis C Virus Infection Beyond the Liver. sis and treatment of xerostomia (dry mouth). YJCGH. 2010;8(12):1017-1029. Odontology. 2009;97(2):76-83. 28. Machado J, Reis PP, Zhang T, et al. Low preva- 40. Proctor G. The of salivary secretion. lence of Human Papillomavirus in oral cavity car- Periodontol 2000. 2016;70:11-25. cinomas. Head Neck Oncol. 2010;12(March):1-6. 41. Walsh LJ. Clinical aspects of salivary biology for 29. Campisi G, Giovannelli L. Controversies sur- the dental clinician. Int Dent South Africa (Aus- rounding human papilloma virus infection, tralasian Ed. 2007;2(3):16-30. head & neck vs , implications for prophylaxis and treatment. Head Neck Oncol. 2009;1:8(March):1-7. 30. Daley E, Dodd V, Debate R, et al. Prevention of HPV-related oral cancer : assessing den- tists’readiness. Public Health. 2014;128(3):231- 238. 31. Ryerson AB, Peters ES, Coughlin SS, et al. Bur- den of Potentially Human Papillomavirus- associ- ated of the Oropharynx and Oral Cavity in the US , 1998-2003. Cancer. 2008;113(No- vember):2901-2909. 32. Gillison ML, Chaturvedi AK, Lowy DR. HPV Pro- phylactic Vaccines and the Potential Prevention of Noncervical Cancers in Both Men and Wom- en. Cancer. 2008;13(November):3036-3046. 33. Makihara H, Goto M, Watanabe H, et al. Oral and Maxillofacial Surgery Cases Age-related

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