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Home , Coxsackie A virus, Herpes labialis, Leukoplakia, Oral mucocele

Oral and Maxillofacial Viral

Stephen Porter, Jair C. Leão, and Luiz Alcino Gueiros

Abstract Keywords A wide spectrum of viral infections can affect Viral diseases • Viral infections • the and allied structures. In most • • HIV • HPV instances, these give rise to short-term local illness (e.g., infections in Contents immunocompetent hosts); however, infections Introduction ...... 2 such as Human Immunodeficiency Herpes Viruses ...... 2 (HIV), Epstein Barr (EBV), and the (HSV-1 and HSV-2) ...... 2 oncogenic types of Human Papillomavirus ...... 6 (HPV) can cause significant orofacial disease Ramsay Hunt Syndrome ...... 7 that will increase patient morbidity and possi- Epstein Barr Virus ...... 8 ...... 10 bly lead to early death. The present chapter Human Herpes Virus 6 ...... 10 details the viral infections that may commonly Human Herpes Virus 7 ...... 10 affect the oral cavity and/or salivary glands in Human Herpes Virus 8 ...... 10 patients worldwide. The epidemiology of viral Coxsackie Viruses ...... 11 infections is ever changing; hence, health care Hand, Foot, and Mouth Disease ...... 11 providers are encouraged to maintain knowl- ...... 12 edge of virally driven infections that may Acute Lymphonodular ...... 13 impact upon the health and clinical care of ...... 13 their relevant specialty. Human Immunodeficiency Viruses ...... 13 Human Papilloma Virus ...... 16 Nononcogenic HPV Disease ...... 16 Oncogenic HPV Disease ...... 17 Viral Infections of the Salivary Glands ...... 19 ...... 19 S. Porter (*) Hepatitis C Virus ...... 20 UCL Eastman Dental Institute, University College HIV Disease ...... 21 London, London, UK e-mail: [email protected] Seasonal Viral Infections ...... 21 J.C. Leão • L.A. Gueiros Emerging Viral Infections ...... 22 Unit, Departamento de Clínica e Odontologia Preventiva, Universidade Federal de Conclusions and Future Directions ...... 22 Pernambuco, Recife, PE, Brazil Cross-References ...... 23 e-mail: [email protected]; [email protected]; [email protected] References ...... 23

# Springer International Publishing AG 2017 1 C.S. Farah et al. (eds.), Contemporary Oral Medicine, https://doi.org/10.1007/978-3-319-28100-1_44-1 2 S. Porter et al.

Introduction destruction and specific induction of a latent immune state. The β-herpervirinae viruses, on The is a common site for primary the other hand, have a long reproductive cycle viral infections particularly those of the human and may become latent in lymphoreticular cells. herpesvirus (HHV) and human papillomavirus CMV is the hallmark of this subfamily, being (HPV) families. More recently, HPV infections capable of inducing a plethora of clinical disor- have received particular attention as oncogenic ders, particularly in immunocompromised indi- types aetiologically linked to increasing numbers viduals. Finally, γ-herpesvirinae have an affinity of cases of oral . None- for T and B lymphocytes, become latent in lym- theless, many other viral infections may be found phoid tissues, and are closely associated with in the oral cavity of humans. This chapter dis- certain malignant diseases. EBV is the typical cusses viral conditions of the oral cavity, includ- member of this subfamily, being associated with ing HHV , HPV, , mumps, acute infection () and , rubella, and those conditions/diseases being causative of malignant diseases that in- associated with HIV and HCV infection. Emerg- clude Burkitt’s and nasopharyngeal ing viral diseases including Ebola and Zika virus carcinoma. are also briefly discussed.

Herpes Simplex Virus (HSV-1 Herpes Viruses and HSV-2)

The human herpesvirus (HHV) are a species- Clinical Features specific family of DNA virus that includes eight Herpes simplex virus 1 (HSV-1) is transmitted via types that can infect humans. The human herpes close contact with infected fluids (usually saliva) viruses are classified into three subfamilies (α, β, or , and tends to give rise to disease of the and γ). The α-herpervirinae viruses are character- mouth and surrounding skin. In contrast, HSV-2 is ized by a relatively short reproductive cycle and usually transmitted by genital-to-genital contact irreversible destruction of infected cells and with infected fluids or lesions and predominantly include HSV1, HSV2, and VZV. β-Herpervirinae gives rise to genital disease. However, HSV-1 can viruses (CMV, HHV6, and HHV7) have a long cause genital disease and HSV-2 can give rise to reproductive cycle and a slow infection process. oral illness as a consequence of acquisition via Finally, γ-herpesvirinae (EBV and HHV8) repli- orogenital contact. Both HSV-1 and HSV-2 lead cate in lymphoblastoid cells and may establish to an initial primary infection with later episodes a latent or lytic infection in B or T lymphocytes. of less severe secondary infection in some, but not This classification is reflectedintheclinicalbehav- all, infected patients (Arduino and Porter 2008). ior of the associated diseases as discussed below. Primary HSV-1 infection typically affects the The human herpes viruses may promote a dis- mouth and arises within 1–2 weeks of acquisition ease state in three distinctive ways: (1) direct of the virus. The clinical features comprise initial destruction of cells and tissues, (2) induction of nonspecific features of malaise, pyrexia, and leth- immune responses, and (3) facilitation of neoplas- argy followed by the eruption of widespread tic transformation. The α-herpervirinae viruses ulceration of the oral mucosa and gingiva (Cun- typically present a short reproductive cycle with ningham et al. 2006). irreversible destruction of infected cells, follow- The ulcers are usually superficial, initially ing the ability to maintain latent infection in the small and spherical but may coalesce to give rise sensorial neural ganglion. Herpes simplex virus is to large sized, irregular outlined ulcers (Fig. 1). within this subfamily and causes rapid infection of The ulceration can arise on any oral mucosal epithelial cells with subsequent latency state and surface; indeed, typically all sites of the mouth recurrent flares, characterizing the direct cellular can be affected. The gingiva becomes swollen, Oral and Maxillofacial Viral Infections 3

Fig. 1 Initial aspect of intraoral herpes simplex infection, palatal ulcers observed 2–3 days following initial symp- with formation in the hard (a). Multiple toms of intraoral herpes simplex (b)

Secondary HSV-1 infection of the mouth affects about 30% of patients with a history of probable primary infection. Many patients present with a likely secondary disease, however, cannot recall having the primary disease (Arduino and Porter 2008; Fatahzadeh and Schwartz 2007). Secondary HSV-1 infection of the mouth typ- ically affects the vermillion of the termed her- pes labialis (commonly known as “cold sores”) (Fig. 3) but can also arise on the perioral or peri- nasal skin. Sole involvement of the mouth (e.g., small numbers of superficial oral mucosal or gin- Fig. 2 Multiple ulcers due to herpes simplex infection gival ulcers) is a very rare manifestation of sec- ondary HSV-1 infection (Figs. 4 and 5). Herpes erythematous, and ulcerated, with ulceration labialis is characterized by a clinical pattern of affecting the free and/or attached gingiva (Fig. 2) paraesthesia, followed by , vesiculation, (and hence may mimic acute necrotizing ulcera- pustule formation, superficial ulceration, and tive – ANUG). The ulceration causes eventual spontaneous healing. The complete clin- notable pain, , dysarthria, and possibly ical disease lasts about 5–7 days (Arduino and . There is usually bilateral cervical Porter 2008). and occasionally a generalized may often, but not always, be macular cutaneous . The precipitated by an identifiable precipitant that may usually spontaneously resolve within 7–10 days, include concomitant illness, (e.g., flu or other although the disease can be severe and prolonged infections) exposure to sunlight or UV light or in immunocompromised individuals (Elad et al. occasionally is associated with particular phases 2010). of the menstrual cycle or pregnancy. Immunosup- Primary HSV-2 infection of the mouth can give pression (e.g., iatrogenic, malignancy-associated rise to a similar clinical picture to that of HSV-1 or HIV-associated) can also lead to the onset of although it has been suggested that the illness may herpes labialis that may be severe and/or pro- be less severe and not as prolonged as that caused longed, but can also involve intra-oral sites by HSV-1. (Fig. 6; Elad et al. 2010). Often patients have 4 S. Porter et al.

Fig. 3 Herpes labialis on the lower lip (Image courtesy of Professor Camile Farah, Perth Oral Medicine & Dental Sleep Centre, Perth WA, Australia)

Fig. 5 Herpetic in patient under chemotherapy for lung

it limited data, that prophylactic acyclovir may lessen outbreaks of recurrent erythema multi- forme minor. Fig. 4 Herpetic gingival (Image courtesy of Profes- sor Camile Farah, Perth Oral Medicine & Dental Sleep Centre, Perth WA, Australia) Diagnosis The diagnosis of primary orofacial HSV-1 is typically based upon the clinical features. The would include ery- recurrences at the exact same site each time, pre- thema multiforme (which tends to recur) or sumably reflecting the location of residency of the immunobullous disease (which tends to arise in herpes simplex virus within the trigeminal middle to late age). Confirmatory investigations ganglion. typically include identification of HSV-1 DNA by Herpes simplex 1 has been suggested to be a molecular means [e.g., polymerase chain reaction causative factor of “idiopathic” lower motor neu- (PCR)]. Demonstration of a four-fold or more rise ron palsy of the facial nerve (i.e., Bell’s palsy), in HSV-1 specific IgG between the although there is no notably strong evidence to acute (i.e., ulcerative) and convalescent phase support this. Indeed, antiviral therapy (e.g., acy- of illness provides a retrospective diagnosis of clovir) is not considered to be a reliable means of primary HSV-1 infection, although this may not resolving Bell’s palsy. Similarly, HSV-1 has been be reliable in immunocompromised patients with proposed to be a precipitant of erythema multi- recurrent bouts of severe HSV-1 driven infection. forme minor as in some instances this has been A full blood cell count should be obtained preceded by herpes labialis. There is some, all be for adults with likely primary HSV infection to Oral and Maxillofacial Viral Infections 5

Fig. 6 Atypical and severe herpes simplex infection in a extensive scab formation (a). Extensive intraoral involve- patient with acute myeloid leukemia. Extraoral aspect with ment with large ulcers limiting solid food intake (b) rule out common causes of immunosuppression be considered for patients with or thought to have (e.g., nonsolid hematological malignancies such immunosuppression, and certainly, those with as leukemia or myeloma) or unknown HIV dis- known immunosuppression should be reviewed ease (with possible lymphopenia) (Arduino and by their attending specialists (Elad et al. 2010). Porter 2008). The acyclovir prodrug valacyclovir and Herpes labialis does not usually warrant inves- (the prodrug of ) are only tigation, as the clinical picture is so characteristic. warranted when there is a need for sustained or Where there is some diagnostic confusion, the frequent administration of an antiviral. Acyclovir identification of HSV DNA via PCR can be help- may be prescribed as tablets or suspension (e.g., ful. The serological investigation is not helpful as 200 mg 5 times daily for 7 days). Intravenous there is no substantial elevation in IgG anti-HSV administration of acyclovir is rarely warranted antibodies between the acute and convalescent (Arduino and Porter 2008). phases of secondary HSV-1 infection. Herpes labialis does not always require treat- ment. A variety of topical nonantiviral prepara- Management tions are available as over-the-counter items for Despite the symptoms being distressing, the man- the symptomatic relief of herpes labialis, but these agement of primary HSV-1 infection can usually are largely untested as to whether they benefit be based upon symptomatic relief alone. Topical patients. Perioral acyclovir cream (5%; applied anti-inflammatory drugs such as benzydamine 6 hourly) or penciclovir cream (1%; applied hydrochloride spray or , or topical 2 hourly) may hasten disease resolution, but anesthetics, such as lidocaine (lignocaine) gel, these agents should be applied to the affected may reduce painful symptoms and facilitate feed- area as soon as possible. Acyclovir is usually ing. Systemic analgesia and antipyretics such as a only of benefit if applied at the vesicular stage, nonsteroidal anti-inflammatory agent such as ibu- while it is suggested that penciclovir may still profen, or paracetamol can be helpful. Affected cause hastening of resolution of symptoms even persons, particularly children, should be encour- if used in the early ulcerative stage. aged to drink fluids. Acyclovir should be pre- All patients with primary or secondary HSV scribed where the symptoms and/or signs are infection should avoid direct contact with other “severe” and early although this will have little individuals to lessen the risk of further transmis- benefit if there is evidence of healing of lesions sion of the causative virus (Mell 2008). (Mell 2008). Acyclovir should, however, always 6 S. Porter et al.

Varicella Zoster Virus Diagnosis The diagnosis of is usually based Clinical Features upon the clinical history and picture. Confirma- Varicella zoster virus (VZV, HHV-3) gives rise to tory viral or serological investigations are rarely a primary infection termed chickenpox and a sec- warranted. ondary infection known as . Infection is transmitted via droplets or close contact with Management lesions (i.e., the cutaneous rash of chickenpox). The treatment of chickenpox is directed toward lessening of symptoms. The pruritus of the rash Chickenpox may be reduced by the local use of calamine or Chickenpox typically arises in preschool children possibly oral antihistamines. Warm baths with and is clinically characterized by the appearance sodium bicarbonate or potassium permanganate of a macular-papular cutaneous rash that rapidly may also be used to relieve the itching. Antivirals evolves into vesicles and later on pustules, accom- are not routinely indicated. panied by and malaise. Within 3–4 days the pustules scab. The fever is generally low and can Shingles be accompanied by mild prodromal symptoms Herpes zoster (HZ) or shingles is caused by such as anorexia and headache. The incubation reactivation of the varicella zoster virus (VZV) in period of VZV (i.e., time from acquisition until ganglia of the cranial nerves or dorsal roots. This the initial manifestation of clinical illness) is reactivation and outbreak are more likely to occur 7–14 days (Anjos et al. 2009). when cellular immunity to VZV is impaired, espe- Complications are uncommon and usually cially by conditions such as immunosuppression, involve secondary infection of skin lesions caused HIV disease, and malignancy. Nevertheless, there by Staphylococcus aureus and Staphylococcus is often no identifiable underlying cause for the pyogenes, leading to , cutaneous ab- onset of the viral eruption. The disease is, however, scesses, and . Rarely, pulmonary or neu- most likely in late life (Portella et al. 2013). rological diseases may follow the clinical course Shingles typically affect the thoracic derma- of chickenpox. tomes via reactivation within spinal ganglia. It Oral lesions are common and may precede manifests as painful eruptions of vesicles with cutaneous involvement, but as the cutaneous later ulceration and prolonged erythema of skin symptoms and signs evolve rapidly and dominate supplied by one or more dermatome of one side of the clinical picture, the oral features may go the thorax or upper abdomen. The pain is intense unnoticed by the patient, carers, or attending cli- and sharp although with time may become more nicians. The oral manifestations are short lasting ache-like. small white-opaque vesicles that rupture and Shingles affecting the trigeminal nerve arises ulcerate, usually on the palate and buccal mucosa independent of thoracic involvement and can (Clarkson et al. 2017). affect any branch of (in order of frequency) the Chickenpox can have a seasonal pattern with ophthalmic, maxillary, or mandibular divisions of outbreaks usually occurring in autumn, coincid- one side (Figs. 7 and 8). Bilateral involvement or ing with the arrival of new populations of suscep- infection of branches of more than one division of tible children. Overall, there are no predisposition one side is extremely rare. Depending upon the distinctions by age, race, or gender regarding branches that are affected, skin lesions similar to infection by VZV. More than 90% of the world those of thoracic shingles can arise and are nota- population is infected by 15 years of age. bly painful (Grahn and Studahl 2015). Although varicella is usually considered a benign The oral lesions of shingles are akin to those of disease, it is important to highlight that about primary HSV-1 infection, i.e., vesicles rapidly 90 children die each year from varicella and its evolve into small superficial ulcers that coalesce complications in the United States. to give rise to larger irregular outlined ulcers. The Oral and Maxillofacial Viral Infections 7 site of involvement will clearly depend on the longer periods (Fig. 9). Confusingly the onset of affected branch, but there is usually a distinct oral shingles may be heralded by pain in one or unilateral distribution of lesions with minor cross- more teeth that have no caries or periapical pathol- over in the midline. The painful ulceration may ogy – the toothache diminishing when the oral last 5–10 days without therapy in the immuno- ulceration commences (Lopes et al. 1998). competent host. In patients with immunodefi- ciency, the signs and symptoms may persist for Ramsay Hunt Syndrome

This is a very rare manifestation of shingles and reflects VZV reactivation within the geniculate ganglion. It is clinically characterized by otitis externa, a unilateral lower motor neuron palsy of the facial nerve, and ulceration of the anterior two-thirds of the and soft palate – all on the same side (i.e., ipsilateral) as the palsy (Grahn and Studahl 2015). The distribution of the oral ulceration reflects the branches of chorda tym- pani. Bilateral Ramsay Hunt syndrome has been described – but is notably rare. Patients with orofacial shingles are generally Fig. 7 Initial aspect of varizella zoster infection involving distressed as a consequence of the severe pain, the maxillary branch of trigeminal nerve

Fig. 8 Herpes zoster in a female patient involving the left Camile Farah, Perth Oral Medicine & Dental Sleep Centre, face and left buccal mucosa (Images courtesy of Professor Perth WA, Australia) 8 S. Porter et al.

Management Unlike primary HSV infection, antiviral therapy is almost always warranted for orofacial shin- gles. Oral acyclovir (e.g., 800 mg, 5 times daily for 7 days) is a typical therapy but sometimes valacyclovir or famciclovir can be used, espe- cially if patients have difficulty in taking medica- tion so frequently and/or the disease is atypical or prolonged. Topical antivirals are of no benefit for shingles of the mouth. Patients with shingles should avoid contact with household members who are elderly or known to be immunocompro- mised as there is a risk of them acquiring VZVand developing chickenpox or shingles. All patients Fig. 9 Sequelae of herpes zoster infection leading to lim- with possible ophthalmic shingles should be ited eye closure referred for a specialist ophthalmology opinion (Werner et al. 2016). although do not have substantial systemic upset such as pyrexia or malaise. Complications of orofacial shingles can include Epstein Barr Virus and meningoencephalitis. The former may affect up to 14% of patients and is Epstein Barr virus (EBV) is a γ-1 herpes virus that characterized by pain that persists for 3 or more gives rise to a variety of different clinical illnesses months after healing of the shingles. It is rare in that include infectious mononucleosis, oral hairy the mouth but can arise on the face, particularly , and a number of malignancies that the forehead. The pain may be an ache through to can affect the head and neck (especially extra- sharp and may be particularly worsened by light nodal natural killer T cell lymphoma (ENKTCL), touch (Portella et al. 2013). Postherpetic neuralgia some other non-Hodgkin and naso- is discussed in a separate chapter. pharyngeal carcinoma). Epstein Barr virus is transmitted via the salivary route (Cohen 2000). Diagnosis The diagnosis of orofacial shingles (including Infectious Mononucleosis Ramsay Hunt syndrome) can usually be made This is the primary infection of EBV and arises based on clinical manifestations alone. Identifica- about 5 weeks following viral acquisition. It typ- tion of VZV DNA and retrospective serological ically occurs in young adults, presumably as a confirmation of VZV infection (i.e., a four-fold or consequence of close nonsexual contact with more rise in specific antibodies between the acute infected persons. The clinical features of infec- and convalescent phases) may be possible, but the tious mononucleosis comprise pharyngitis, levels do not always rise much, particu- pyrexia, cervical lymphadenopathy, and possibly larly in elderly persons and/or those who are nausea and abdominal pain due to hepatitis and immunocompromised (Sauerbrei 2016). It is hepatosplenomegaly. These can be accompanied always prudent to assess the full blood cell count by a pink maculopapular rash that may be more for evidence of unknown neutropenia, leukemia, profound if patients are prescribed ampicillin-type or other white blood cell dyscrasia as just occa- antibiotics. There is often profound lethargy that sionally orofacial shingles will be the first mani- dominates the clinical symptoms (Luzuriaga and festation of an underlying, significant, disease. Sullivan 2010). Oral and Maxillofacial Viral Infections 9

Diagnosis The diagnosis can sometimes be based upon the clinical picture alone, but as this can also arise as a consequence of other infections (see below), formal confirmation is useful. It is confirmed by the identification of an atypical lymphocytosis in a full blood cell count and the detection of anti-EBV antibodies (heterophile antibodies) in serum (also sometimes termed the monospot test or Paul Bunnell test). Abnormal hepatic function may be detected serologically (e.g., liver function tests) in patients with EBV-related hepatitis as part of infectious mononucleosis (Luzuriaga and Sullivan 2010). Fig. 10 Oral associated with oral Glandular fever describes a similar clinical candidosis in a patient with HIV infection pattern to that of infectious mononucleosis that can arise with infection by cytomegalovirus, HIV, mellitus or secondary to corticosteroid inhaler and toxoplasmosis. However, unlike infectious use) (Stojanov and Woo 2015). mononucleosis, there are no detectable high levels of anti-EBV antibodies (i.e., these are Paul Diagnosis Bunnell negative types of glandular fever) in The diagnosis of OHL rests upon histopathologi- these disorders, and indeed it may be possible to cal examination of lesional tissue, which will differentiate them by the detection of IgG anti- demonstrate , acanthosis, possible bodies to HIV or IgM class antibodies to CMV or ballooning koilocytes in the , toxoplasmosis. and a lack of any notable inflammatory infiltrate in the . Immunohistochemistry is essential Management to confirm the presence of EBV-derived . The management of infectious mononucleosis is based upon reducing any painful symptoms. The Management lethargy resolves spontaneously but over several Given its nature and its lack of weeks. Antiviral therapy is not usually warranted, any malignant potential, OHL does not warrant and antibiotics or corticosteroids for pharyngitis treatment. In patients whose immune status or pharyngeal are not typically employed improves (e.g., cessation of iatrogenic immunosup- (Oliveira et al. 2012). pression or antiretroviral therapy (ART; also some- times termed ARV-related HIV disease status)), Oral Hairy Leukoplakia lesions often regress (Stojanov and Woo 2015).

Clinical Features Other Disorders Caused by Epstein Barr Oral hairy leukoplakia (OHL) is a secondary Virus infection of EBV.It manifests as adherent, homog- Epstein Barr virus is the cause of several types of enous, sometimes hair-like, white patches of the non-Hodgkin’s lymphoma (e.g., Burkitt’s lym- lateral aspects of the tongue as well as sometimes phoma, and extranodal natural killer T cell lym- the dorsal or ventral surfaces (Fig. 10). The lesions phoma [ENKTCL]) or the nonkeratinizing type of are nonpainful and not potentially malignant. . Of relevance to the Oral hairy leukoplakia arises in individuals who mouth, about 50% of B cell type Non-Hodgkins are immunocompromised (e.g., undiagnosed or lymphoma of HIV disease are EBV-associated. untreated HIV infection, iatrogenic immunosup- Extranodal natural killer T cell lymphoma usually pression, and rarely a feature of diabetes arises in the nose or sinus but can cause a notable 10 S. Porter et al. destruction of the hard and/or soft palate, upper gingiva, and posterior tongue (Odumade et al. 2011). These tumors are covered in more detail in separate chapters on ▶ Head and Neck Tumors and ▶ Non-Odontogenic Bone Pathology.

Cytomegalovirus

Cytomegalovirus (CMV) is a beta herpesvirus. It is transmitted both horizontally following expo- sure to body fluids, including saliva, urine, and cervicovaginal secretions. Salivary transmission within families is common, probably from young children passing it to nonimmune family mem- bers. CMV infection rarely gives rise to oral dis- ease and while it has been suggested that it may give rise to salivary gland swelling there is actu- ally little supportive evidence for this claim. Most perinatally infected infants do not have Fig. 11 CMV-related ulcer in a patient with acute myeloid leukemia any symptoms although immunocompetent adults can sometimes develop glandular fever-like symp- These should not be prescribed for minor CMV toms. Of note, however, transplacental transmission infection in the immunocompetent patient. of CMV can result in fetal damage including hepatosplenomegaly, jaundice, CNS abnormali- ties, and growth retardation (Cannon and Davis Human Herpes Virus 6 2005). While the majority of infected newborns will be asymptomatic, 30% will develop severe (HHV-6) is a beta herpes hearing impairment. of the primary virus. It gives rise to a disorder termed exanthema dentition can also arise with congenital CMV subitum, characterized by pyrexia, skin rash, and infection. occasionally seizures and encephalitis. It may In immunocompromised patients (for example, be transmitted via saliva, but as it has no oral man- HIV disease or iatrogenic immunosuppression), ifestations, it is of little relevance to oral health care. CMV can cause unusual superficial oral mucosal ulcers that may have a star-like (stellate) appear- ance, particularly on the tongue (Fig. 11; Torres Human Herpes Virus 7 et al. 2004; Mainville et al. 2015). fi CMV can cause signi cant disease in the Human herpesvirus 7 (HHV-7) is a beta virus that immunocompromised host, for example, infec- can be transmitted via saliva. It may give rise to tion following renal allografts can cause chronic exanthema subitum, but it has no clinical impact rejection while coronary artery stenosis can arise upon oral health care. in patients infected following cardiac transplanta- tion. CMV pneumonitis is a of CMV infection following lung transplantation, and reti- Human Herpes Virus 8 nitis (with possible visual loss) can be caused by CMV infection in HIV disease (Patel et al. 2012). Human herpesvirus 8 (HHV-8) is a gamma Ganciclovir and valganciclovir are the antivi- herpes virus that causes Kaposi’s sarcoma (KS), rals typically used for severe CMV infection. Oral and Maxillofacial Viral Infections 11 pleural effusion lymphoma (PEL), and multi- centric Castleman’s disease. Its predominant rele- vance to oral disease and is its causative association with KS. HHV-8 can be transmitted both sexually and less commonly nonsexually (e.g., via saliva, other fluids, including blood) (Leão et al. 2002). Kaposi’s sarcoma of the mouth arises in immu- nocompromised groups, particularly those with HIV disease that has not been identified, or not been treated with antiretroviral therapy (ART). Kaposi’s sarcoma of the oral tissues typically manifests as a red, blue, or purple macule, , or nodule and typically arises at the hard-soft palate junction of one side. The lesions spread and can be destructive (Fig. 12). Occasionally KS initially develops at sites other than the palate, Fig. 12 Oral Kaposi’s sarcoma presenting as a large ulcer- for example, the maxillary gingiva. As the disease ated erythematous nodule involving upper gingiva and buccal mucosa in a patient with late stage HIV disease progresses, the affected site becomes ulcerated and necrotic and gingival involvement can lead to tooth mobility and loss (Fatahzadeh and Coxsackie Viruses Schwartz 2013). Occasionally KS can manifest as a nonpigmented and thus looks like an Hand, Foot, and Mouth Disease oral squamous cell carcinoma or non-Hodgkin’s lymphoma. Hand, foot, and mouth disease (HFMD) is a com- The diagnosis of KS rests upon histological and mon viral and exanthematous illness, typically immunohistochemical examination of lesional tis- affecting infants and children between 3 and sue while staging of disease follows typical radio- 10 years of age. The most common virus involved logical investigation. Certainly, all patients with is coxsackie virus A16, but other viruses such as oral KS require investigation of any unidentified coxsackie viruses A5, A7, A9, A10, B2, B5, and underlying immunosuppression – which in almost enterovirus 71 can also cause HFMD (Solomon all instances will reveal previously unknown HIV et al. 2010). The disease usually arises as out- infection (Schneider and Dittmer 2017). breaks that are most frequent in the summer In the past, KS was a common oral manifesta- periods. Small epidemics are frequently reported tion of HIV disease but as a consequence of the among schoolchildren or those attending nurser- wide increasing availability of effective ART the ies. Indeed, it may spread through an entire school of this tumor has greatly reduced in and also affect parents, carers, and teachers (Shin HIV-infected groups across the globe. Of note, et al. 2010). HIV-associated KS can regress following the The transmission takes place through fecal- introduction of ART, and similarly, the emergence oral contact or via inhalation of respiratory drop- of oral KS in patients receiving ART can be an lets; however the direct interaction with cutaneous indication that therapy is failing or the patient in lesions can also cause disease transmission. The not remaining compliant in taking the medication. incubation period is 3–7 days and the disease is The specific management of local or wide- most contagious in the first week of illness. Nev- spread KD necessitates local radiotherapy and/or ertheless, some individuals can be contagious for chemotherapy and is covered elsewhere in days or weeks after resolution of their symptoms this book. and signs. The virus is present for about 12 S. Porter et al.

Fig. 13 Hand Foot and Mouth disease. Lingual ulceration Professors Marcio Lopes and Alan Santos-Silva, (a), palmar erythematous areas (b), and vesiculation of the Orocentro, FOP/UNICAMP, Brazil) dorsal surface of the foot (c). (Images courtesy of

6–8 weeks in feces, and about a week in the The diagnosis is typically based upon the clin- respiratory system. ical picture. Treatment is mainly supportive via Hand foot and mouth disease usually presents hydration, topical, or systemic analgesics and with fever, reduced appetite, sore throat, and mal- antipyretics (e.g., paracetamol or ibuprofen). The aise. After one to 2 days, numerous vesicles and disease has no notable long-lasting consequences. oral ulcers emerge, varying in number from 1 to 30 lesions. The most commonly affected sites are the buccal mucosa, labial mucosa, and tongue Herpangina (Fig. 13a), but any site of the oral mucosa can be affected. Such vesicles are usually 2–7mm Herpangina is caused by a type A coxsackie group in diameter, can be larger than 1 cm, but gradu- infection. It is most frequent in children. The virus ally disappear after a period of about 1 week is transmitted via saliva or occasionally fecal-oral (Aswathyraj et al. 2016). route. As with HFMD, infection tends to arise in The palms of the hand and soles of the feet are epidemics. In cold climates, this is often in the usually affected following the oral lesions summer or autumn while in tropical countries it (Fig. 13b). The eruption consists of vesicles or can occur in any season (Puenpa et al. 2014). small at the distal flexor aspect of the Symptoms arise 2–10 days following exposure fingers or toes (Fig. 13c). Rarely, the skin of the to the virus and comprise fever, sore throat, head- knees, elbows, and genital area can be affected ache, dysphagia, and malaise. After 24–48 h, a (Aswathyraj et al. 2016). diffuse erythema and vesiculation of the posterior region of the oral mucosa and oropharynx occur. Oral and Maxillofacial Viral Infections 13

There are numerous small vesicles, particularly the hands and multiple petechiae of the torso or the soft palate and/or tonsillar pillars, which rup- extremities. ture quickly to give rise to shallow and painful Oral lesions can arise in about 20% of affected ulcers. The clinical picture resolves spontane- individuals as dark-red macules or petechiae ously after 7–10 days (Scott and Stone 2003). (Forchheimer sign) on the soft palate. The oral As with HFMD, the diagnosis of herpangina is features appear simultaneously with cutaneous usually based upon the clinical picture, while eruptions (Tyor and Harrison 2014). therapy is directed toward ensuring adequate In most instances, the acute illness of rubella hydration, appropriate analgesia, and antipyretics. is of little clinical significance. However, con- genital rubella syndrome is significant – causing malformations, premature birth or spontane- Acute Lymphonodular Pharyngitis ous abortion in severe cases. Newborns with con- genital rubella are extremely contagious. Clinical This is caused by Coxsackie virus A10. It features in infants may include microcephaly, typically affects children and young adults, intellectual disability, developmental delay, cloudy although occasionally older individuals can also corneas, and seizures, among other severe devel- be included. The infection has an incubation opmental limitations (Tyor and Harrison 2014). period of about 5 days following which there is Treatment of the acute disease is generally not sore throat, pyrexia, mild headache, and anorexia. required. Antipyretic and antipruritic agents may Oral lesions develop about 2–3 days after onset of be helpful in patients with significant fever and the systemic features and comprise a small num- symptomatic skin involvement. Passive immunity ber of discrete white to yellow on the can be provided by administration of rubella uvula, soft palate, palatoglossal folds, and poste- human immunoglobulin. If the immunoglobulin rior pharyngeal wall. The lesions are self-limiting is administered during the first days of exposure, and usually regress in about 10 days without any it will lessen the severity of the infection. Double blistering or ulceration. Therapy should be aimed dose vaccination is recommended with measles, at reducing any pyrexia and ensuring adequate mumps, and rubella, the first dose being between hydration (Steigman et al. 1962). 12 and 15 months of age and the second between 4 and 6 years.

Rubella Human Viruses (RV) is a member of the Togaviridae family. The virus is transmitted via the droplet Human immunodeficiency virus (HIV) comprises route but of concern vertical transmission from 2 main RNA viruses (HIV-1 and HIV-2) that tend an infected mother transplacentally during the to give rise to a similar clinical picture. This first semester of pregnancy can cause congenital infection came to clinical and public attention in rubella syndrome (CRS). The risk of rubella infec- the early 1980s and since then has gone on to tion is however low in view of the high uptake of infect, and kill, many millions of individuals vaccination (together with mumps and measles across the globe. However, in the past decade immunization) (Tyor and Harrison 2014). the numbers of persons acquiring infection has Rubella has an incubation period of 2–3 weeks; begun to fall as a consequence of changing life- following which a cutaneous rash develops, usu- style and/or awareness of methods of avoiding ally on the face that gradually evolves on all acquisition (i.e., barrier methods of contracep- cutaneous surfaces. The rash is accompanied by tion), while increasing availability of effective lymphadenopathy of the cervical region as well therapy (antiretroviral therapy – ART) has led to as headache, low-grade fever, malaise and mild a fall in the mortality rate of infected persons , and rarely transient arthralgia of (Patton et al. 2013). Nevertheless, as of 2015, 14 S. Porter et al. there are 37 million individuals across the globe living with HIV disease. The virus is principally transmitted by sexual, parenteral, or vertical (transplacental) routes (Pinheiro et al. 2009). While infection was ini- tially observed in gay men and recipients of blood and blood products, the majority of new infections arise as a consequence of heterosexual transmis- sion, although sex between men remains a risk factor. Vertical transmission has greatly decreased in the past two decades as a consequence of improved HIV disease surveillance (Patton 2016). Human immunodeficiency virus gives rise to clinical disease principally as a result of infection and later loss of CD4+ T lymphocytes that are key to cell-mediated immunity. The fall in CD4+ T lymphocytes increases the risk of opportunistic infection particularly by viruses, mycobacteria, Fig. 14 Pseudomembranous candidosis in HIV disease. and fungi. As a result, patients without appropri- Erythematous plaque intermingled with white patch as a ate ART can manifest a spectrum of systemic clinical presentation of oral candidosis in a patient with HIV infection under ART infections that include Pneumocystis pneumonia, mucocutaneous and visceral Kaposi’s sarcoma, The most common oral manifestations of herpes zoster infection and candidal infection as HIV disease are candidosis (usually pseudo- well as a very wide range of other infections, membranous) (Fig. 14), hairy leukoplakia, and virally driven malignancies, and neurological dis- Kaposi’s sarcoma. Each of these is detailed in orders (Northfield et al. 2005). other sections of this book. The likelihood of Awide range of oral disorders can arise in HIV each of these arising in the mouth is directly disease, these reflecting the failure of cell- linked to the degree of immune dysfunction that mediated immunity. Indeed prior to the availabil- occurs (typically determined by peripheral blood ity of ART, it was likely that all individuals CD4+ T cell count). infected with HIV would ultimately develop oral Recall also that early HIV infection (usually at disease (Ficarra 1997). However, as ART is the time of generating of anti-HIV antibodies – increasingly available (90% of all HIV-infected termed seroconversion) can give rise to glandular individuals in many countries now have access fever like symptoms and signs. to this) and is highly effective in lessening HIV The oral manifestations that are potentially burden, the frequency and severity of oral disor- possible if HIV disease either goes undertreated ders likely to be observed in HIV-infected indi- or fails to be treated for different reasons are wide viduals have dramatically fallen over the past ranging and are summarized in Table 1. The char- decade (Patton et al. 2013). In turn, a spectrum acter, severity, and frequency of the oral disorders of oral symptoms and signs can occur as a conse- that can arise are dependent upon the stage of quence of adverse side effects of ART. Neverthe- disease, and the type of ART a patient may be less, not all individuals with HIV disease are receiving (Patton 2016). aware that they are infected, and not all patients The management of the underlying HIV infec- can tolerate or take ART hence there will always tion is out of the spectrum of an oral medicine remain individuals who develop oral features of specialist, as is the management of the vast major- HIV disease. ity of infections and tumors of HIV disease. Oral and Maxillofacial Viral Infections 15

Table 1 Oral mucosal disease in HIV infection. Tissue Clinical presentation Disease Oral mucosal Ulceration Herpes simplex disease Herpes zoster Cytomegalovirus Mycobacterium tuberculosis Mycobacteria other than tuberculosis (MOTT) Treponema pallidum (e.g., lues maligna) Gram negative bacterial infection Toxoplasmosis Aspergillosis secondary to drug therapy Kaposi’s sarcoma non-Hodgkin’s lymphoma Recurrent oral ulceration of unknown cause White patches Pseudomembranous candidosis Chronic hyperplastic candidosis Mucormycosis Oral hairy leukoplakia Condylomata (i.e., HPV infection) Koilocytic (probable HPV infection) Pigmented lesions Addisonian pigmentation – secondary toadrenal cortex hypofunction (e.g., by CMV, , or mycobacteria) or drug therapy (e.g., ketoconazole) Hypermelanotic pigmentation secondary to nucleoside reverse transcriptase inhibitor therapy Borrelia hanselae infection (Cat scratch disease) Kaposi’s sarcoma Gingival and Severe acute gingivitis Acute necrotizing ulcerative gingivitis (necrotizing periodontitis) Salivary gland Salivary gland HIV (i.e., BK virus infection) disease enlargement due to: Parotid lymphadenopathy Intra-glandular malignancy (e.g., non-Hodgkin’s lymphoma, Kaposi’s sarcoma) Acute suppurative secondary to ART Xerostomia due to: HIV salivary gland disease Protease inhibitors or other drug therapy (e.g., anxiolytics and antidepressants) Altered sensation Dysgeusia (e.g., due to protease inhibitors) Trigeminal neuropathy Other cranial nerve anomalies

Certainly however, all patients with known HIV lumps in the mouth, or salivary gland swellings) should be given appropriate advice to prevent that persist for 2 or more weeks. Finally, all oral common oral diseases such as caries, gingivitis, health care workers should be aware of the com- and periodontitis. They should also be encouraged mon oral manifestations of HIV disease as these to consult a clinician if they develop unusual may be the first and only manifestation of symptoms or signs (e.g., painful ulceration, unknown or undiagnosed HIV infection. 16 S. Porter et al.

Human Papilloma Virus proteins being identified by immunohistochemi- cal studies. Genotyping of the virus is possible, Human papilloma viruses (HPV) comprise a but it is not a routine diagnostic investiga- group of DNA viruses of approximately 200 differ- tion (Pinheiro et al. 2011). ent sub-types. These viruses are classified Squamous papillomas of the oral mucosa according to their tissue tropism into dermatotropic require removal either via scalpel surgery or laser and mucosotropic. They can also be classified surgery (Stojanov and Woo 2015) incorporating a as oncogenic (i.e., cancer causing) and non- rim of normal mucosa in the excisional . A oncogenic. Human papilloma virus infection search for the possible source of the causative gives rise to a wide range of usually benign skin virus is rarely helpful, but patients should be or squamous mucosal lesions. These include plan- advised to have any other managed by tar warts, flat warts, genital condyloma acuminata appropriate specialists – and to avoid biting any and oral papillomas. existing ones that they may have on their skin. Human papilloma virus is typically transmitted by direct contact with an infected lesion, for Multifocal Epithelial Hyperplasia example, squamous papillomas may arise as a Multifocal epithelial hyperplasia (MEH), some- result of autoinoculation following biting of a times termed Heck’s disease, gives rise to multiple of the skin. Similarly, oral or genital condy- soft, flat, or rounded elevated nodules and is prob- loma may arise as a consequence of ably the most clinically significant HPV disorder (Beder Ribeiro et al. 2014). Nonsexual transmis- of the mouth (Fig. 20). The lesions develop in sion via oral fluids or food utensils may account early childhood, are asymptomatic, persist for for the acquisition of multifocal epithelial hyper- several years, and regress spontaneously. The plasia (see later). lesions of MEH occur exclusively on the oral mucosa, being commonly located on the mucosa of the lower lip and the buccal mucosa (Said et al. Nononcogenic HPV Disease 2013). Lesions can arise at other sites, but the involvement of the floor of the mouth, soft palate, Squamous Papilloma and Related and oropharynx is unusual. Lesions Multifocal epithelial hyperplasia is rare but The most common oral HPV lesion is squamous tends only to occur in certain ethnic and racial papilloma (SP). These manifest as small finger- groups. It is particularly found among Inuit like projections resulting in a lesion with a rough Indians resident in North, Central and South or cauliflower-like surface (Fig. 15). HPV 6 and America, Eskimos from Greenland and North HPV 11 are the most commonly isolated geno- Canada, and descendants of Khoi-San in South types in these lesions (Stojanov and Woo 2015). Africa. Multifocal epithelial hyperplasia is more Condyloma acuminata – warts possibly acquired common in children and adolescents than in adults sexually (e.g., via oral sex and possibly maternal in most examined populations, although in transmission) gives rise to similar lesions to those Eskimos MEH may be more common in adults of SP (Fig. 16). HPV types 2, 6, and 11 seem to be than in children (Said et al. 2013). the more commonly isolated genotypes of condy- Many HPV genotypes have been detected in loma acuminata. HPV 1 and 57 (sometimes also MEH lesions although types 13 and 32 are the 6 and 11) associated verucca vulgaris, often clin- most commonly associated types, representing ically indistinguishable from SP and condyloma 75–100% of the isolated HPV (Padayachee and acuminata, may also arise on the oral mucosa van Wyk 1991). The clustering of MEH in socio- (Fig. 17). economically deprived groups and ethnically The diagnosis of HPV-related isolated warty- related cohorts suggest that both acquired and like masses can be confirmed by histopathology genetic factors may underlie transmission and of lesional tissue (Figs. 18 and 19) with the viral acquisition of causative HPV genotypes. Oral and Maxillofacial Viral Infections 17

Fig. 15 Squamous papilloma on the soft palate (Image Fig. 16 Notable HPV-induced condylomata of the upper courtesy of Professor Camile Farah, Perth Oral Medicine & gingivae Dental Sleep Centre, Perth WA, Australia)

The diagnosis of MEH can usually be based upon the clinical picture sometimes aided by a review of the patient’s genetic background. Histopathology will confirm the presence of epi- thelial proliferation typical of HPV and immuno- histochemistry of lesional tissue can identify HPV-derived proteins. Genotyping may be possi- ble but is not a routine investigation and not likely to be helpful to the management of the disease. There is no specific management protocol for MEH, although unsightly lesions and those that lessen oral function should be removed. Topical therapies such as imiquimod or interferon-2α may be of some benefit, but there are no detailed stud- ies of the precise efficacy for this disorder. It is however important to inform patients and their carers that lesions usually spontaneously regress with time and that the disease is not known to be potentially malignant (Said et al. 2013).

Oncogenic HPV Disease

Oncogenic types of HPV are now recognized as a cause of some squamous cell carcinoma, particu- Fig. 17 Verruca vulgaris on the buccal mucosa (Image larly of the posterior tongue, tonsillar area, and courtesy of Professor Camile Farah, Perth Oral Medicine & Dental Sleep Centre, Perth WA, Australia) upper . HPV-related oropharyngeal squa- mous cell carcinoma (OPSCC) seems to be a distinct disease differing to head and neck carci- of age and have no history of notable tobacco nomas associated with tobacco and alcohol intake and/or alcohol use. Furthermore, the outcome of (Sedghizadeh et al. 2016; Mazul et al. 2017). treatment of HPV-related OPSCC is better (80% Affected patients tend to be male, under 50 years survival at 5 years) compared with due to alcohol and tobacco (40–50% 5-year 18 S. Porter et al.

Fig. 18 Squamous papilloma at low magnification (a) courtesy of Professor Camile Farah, Perth Oral Medicine and higher magnifciation (b) demonstrating fibrovascular & Dental Sleep Centre, Perth WA, Australia) cores surrounded by benign squamous (Images

Fig. 19 Verruca vulgaris at low magnification (a) and Farah, Perth Oral Medicine & Dental Sleep Centre, Perth higher magnificaiton (b) with clear koilocytes in upper WA, Australia) epithelial layers (Images courtesy of Professor Camile Oral and Maxillofacial Viral Infections 19

across all populations. HPV-related oropharyn- geal carcinoma is discussed in more detail in a separate chapter on ▶ Head and Neck Tumors.

Viral Infections of the Salivary Glands

Mumps

Mumps, sometimes known as epidemic , is an acute self-limiting disease caused by the mumps virus – a member of the Rubulavirus Fig. 20 Oral papillomatosis in extensive labial involve- ment in a patient with HIV infection genus of RNA Paramyxoviruses. In view of the availability of an appropriate vaccine, the out- breaks of disease are much less common than in the past. Prior to this, mumps was likely to arise as survival rate). In the US, Finland, Sweden, Den- outbreaks in kindergartens and schools and thus mark, Netherlands, UK, Canada, Australia, and clinical infection was most likely in 5–16-year-old elsewhere, the incidence of HPV-positive OPSCC children. The virus is transmitted via the droplet has climbed greatly in the past 30 years, in some route with patients being infectious about 48 h instances by 225%. The exact reason for this before the onset of the salivary gland swelling change in the epidemiology of OPSCC is unclear. and for a further 9–10 days. The infection has an The causative genotypes of HPV-related incubation period of 15–21 days. OPSCC are HPV 16 and sometimes HPV 18. Of Infected individuals develop an initial pyrexia note HPV 16 is the predominant genotype associ- and malaise that is soon followed by swelling of ated with cervical cancer of females and one or both parotid glands. The submandibular anogenital of males. It is suggested that glands, and rarely the sublingual glands, can the HPV causing oropharyngeal malignancy has become swollen and together with cervical been acquired sexually and may reflect numbers lymphadenopathy can cause notable swelling of of sexual partners (more than four may increase the neck. Rarely sublingual gland enlargement the likelihood of malignancy), but there is no can cause an elevation of the floor of the mouth striking evidence that the virus is acquired via and tongue with resultant dysarthria and/or dys- orogenital or oroanal contact (despite both being phagia (Wilson et al. 2014). All salivary gland likely). The precise reason why HPV-related swelling diminishes after about 9 days. Of note, malignancy has emerged over the past three but rare, there can be a reversible weakening of decades is unknown, but it does not seem to reflect the facial nerve in association with parotid any change in the sexual lifestyle of individuals enlargement of mumps. or populations. It is quite possible that HPV- Mumps can give rise to a multitude of systemic associated OPSCC is simply behaving like any manifestations. Orchitis (i.e., infection of the other sexually transmitted disease – the more an testicles) can arise 4–5 days after the onset of infection is within a population the greater the parotid enlargement, causing local usually unilat- chance that an individual will ultimately develop eral pain that resolves after a few days. Orchitis clinically detectable disease. In view of the nota- tends to occur in postpubertal boys but is not a ble rise in the number of persons developing common cause of late infertility. A lymphocytic HPV-related oral and pharyngeal cancer, it or viral giving rise to headache and would perhaps seem appropriate that vaccination photophobia can either arise in the absence of any in both boys and girls against the oncogenic types parotid enlargement or follow salivary gland swell- of HPV (particularly 16 and 18) be undertaken ing. Rarely mumps causes retrobulbar neuritis or 20 S. Porter et al. encephalitis. Deafness is a rare but possible com- plication of mumps. Mumps-associated pancreati- tis can cause transient upper abdominal pain while hepatic, breast, cardiac, or joint infections are pos- sible. These are uncommon and not likely to give rise to long-term complications (Tyor and Harrison 2014). Although rare now as a consequence of effective vaccination, mumps in the first trimester of pregnancy can lead to spontaneous abortion. The diagnosis of mumps is almost always based on the clinical picture. The detection of mumps-specific IgM or IgA class antibodies can provide confirmatory evidence of recent infection while viral culture from saliva, urine, or cerebrospinal fluid (CSF) is possible but it is rarely justified (Tyor and Harrison 2014). There is no specific therapy for mumps. Treat- ment is directed toward lessening any pain and/or pyrexia. Fluid intake should be maintained. While suggested as useful, there are no supportive data Fig. 21 Bilateral parotid gland enlargement in Hepatitis C that systemic corticosteroids will reduce any pain- virus disease ful salivary gland swelling. Mumps is a preventable infection, with vacci- patients may develop painless or painful swelling nation being provided at the same time as that for of one or both parotid glands (Fig. 21). measles and rubella. The clinical and economic The histopathological features of HCV- fi bene ts of the mumps, measles, and rubella vac- associated sialadenitis have similarities to those cination are unfortunately well illustrated by the of Sjögren’s syndrome, there being lymphocytic instance of nonimmunized children and adults infiltrate of salivary tissue in both. However, who have developed mumps-related neurological whereas the infiltrate is periductal in the latter, in disease necessitating hospitalization (Tyor and HCV sialadenitis it is pericapillary (Ko et al. Harrison 2014). 2012). In addition, there is a more dominant cyto- toxic T cell infiltrate in HCV disease than in Sjögren’s syndrome. Nevertheless, the precise Hepatitis C Virus pathogenesis of HCV-related salivary gland dis- ease remains unclear, particularly as the presence Hepatitis C virus (HCV) is an RNA virus trans- of HCV RNA in saliva does not correlate with mitted primarily by parenteral and sometimes via clinical or histopathological evidence of salivary sexual (although not orogenital) or vertical routes. gland dysfunction. Persons who inject drugs (PWID) are at notable HCV infection may occasionally give rise to risk of acquiring HCV. non-Hodgkin’s lymphoma (usually low-grade B Unlike other hepatotropic viruses, HCV fre- cell malignancies), indeed the salivary glands are a quently gives rise to a wide spectrum of extrahe- common site of lymphoma in HCV-infected indi- patic manifestations that include salivary gland viduals with sicca-like symptoms (Sherman and disease. Hepatitis C virus-associated salivary Sherman 2015). There is however, no association gland disease arises in as many as 80% of infected between HCV infection and the pathogenesis of patients (Sherman and Sherman 2015). Sjögren’s syndrome. Association between HCV Xerostomia is the predominant symptom of infection and the development of oral HCV-associated salivary gland disease although Oral and Maxillofacial Viral Infections 21 has been suggested for many years but at present virally driven opportunistic infection (Burger- there remains no substantial evidence that lichen Calderon and Webster-Cyriaque 2015). planus is driven by HCV. Certainly, interferon There is little information regarding the spe- gamma therapy for HCV infection can cause the cific management of HIV salivary gland disease emergency of oral and cutaneous lichen planus. and associated cystic swellings. Clinical signs are The management of HCV infection is out with usually nonprogressive, and hence therapy is only the remit of the oral medicine specialist although indicated if there is notable cosmetic deformity or the management of xerostomia should be similar xerostomia. Antiretroviral therapy may cause to that of other causes of oral dryness and is cov- some reduction in swelling, and while it has ered in great detail in the chapter on ▶ Salivary been suggested that ART will reduce the swelling Gland Disorders and Diseases. of HIV salivary gland disease, there is some evi- dence that protease inhibitors of ART may increase swelling (sometimes as a consequence HIV Salivary Gland Disease of fat accumulation within the gland) and lessen salivary secretion (Syebele 2010; Ghrenassia et al. Salivary gland manifestations can arise in up to 2015). Other therapies that have been suggested 10% of adults and children with untreated HIV include repeated aspiration, tetracycline sclerosis, infection (Rath et al. 2015). A variety of lesions or surgical removal of the enlarged gland. Exter- can underlie the salivary gland disease of HIV nal radiation (e.g., 8–10Gy) can cause transient infection and include HIV salivary gland disease improvement, although higher doses (e.g., 24Gy) per se, bacterial sialadenitis, intraparotid lymph- can cause resolution of swelling for at least several adenopathy, primary or metastatic non-Hodgkin’s years – without causing severe xerostomia. lymphoma, or Kaposi’s sarcoma. There have been rare reports of sialolithiasis possibly secondary to atazanavir (that has been linked to renal and Seasonal Viral Infections biliary lithiasis) (Lê et al. 2013), formation of the sublingual gland, and submandibular gland Influenza, commonly known as flu, is a viral swelling due to cytomegalovirus infection as febrile disease usually benign and self-limiting part of Immune Reconstitution Syndrome (IRIS) caused by a RNA virus, Myxovirus influenzae. (Sheikh et al. 2013). Symptoms often present an acute onset and HIV salivary gland disease is a distinct disor- include fever, headaches, myalgia, anorexia, shiv- der characterized by recurrent and/or persistent ering, and chills, as well as respiratory symptoms major salivary gland enlargement and xerostomia. such as cough, sore throat, and coryza. Disease The parotid glands are most frequently affected, usually lasts for 7 days, fever being usually the there often being a profound bilateral enlargement most significant symptom. (Schiödt et al. 1992). Salivary gland disease tends There are three main types of influenza to arise in late HIV infection, although occasion- virus: A, B, and C. Influenza C virus is associated ally can be the first manifestation of unknown with mild respiratory symptoms and is not asso- HIV infection. It is usually part of a more gener- ciated with epidemics. The influenza A and B alized disorder termed Diffuse Infiltrative Lym- virus are associated with seasonal outbreaks, and phocytosis Syndrome (DILS) characterized by the later can eventually cause major pandemics CD8+ T cell infiltration of the lungs, salivary (SteelFisher et al. 2010). The influenza A virus glands, and lacrimal glands (Ghrenassia et al. presents with high variability and can be classified 2015). There is increasing evidence that the sali- according to surface proteins hemagglutinin vary gland inflammation is driven by infection and neuraminidase; the subtypes A(H1N1) and with BK polyomavirus (BKV) and thus HIV sal- A(H3N2) are currently more common in humans. ivary gland disease might be considered to be a The virus replicates in the epithelial columnar cells of the respiratory tract, mix with respiratory 22 S. Porter et al. secretions and spread into small aerosol particles been instances of this arising in individuals who generated during talking, coughing, and sneezing, have travelled out of these areas. This disorder so one infected individual may transmit the virus (Ebola Virus Disease; EVD) causes sudden onset to several other people. In addition, the influenza of high fever, headache, anorexia, nausea, abdom- viruses present a significantly elevated variability, inal pain, and later hemorrhagic disease – includ- which turn them into a unique cause of recurrent ing spontaneous gingival bleeding (Scully and annual epidemics, and eventually, pandemics. Samaranayake 2016). Similarly, the RNA Zika Because of this variability, previous exposition Virus (ZIKV), transmitted by the female genre to one virus does not offer protection to a new of the Aedes mosquito, was initially described in viral challenge. the Ugandan Zika forest in Africa but there have Clinically, the disease presents with an acute been recent outbreaks in Micronesia and Brazil, onset fever, usually above 38 C, following myal- with affected persons being reported in the USA. gia, sore throat, fatigue, headache, and cough. This infection, among other features, can give rise Fever usually last for 3 days and is followed by to Guillain Barre-like disease that may affect respiratory symptoms, such as dry throat, hoarse- facial motor function as well as microcephaly as ness, and retrosternal burning when coughing. a consequence of in utero acquisition of the virus Furthermore, red eyes, tearing, and widespread (Ioos et al. 2014, Leão et al. 2017). Finally, the redness of the mucosa are observed, together virus (CHIKV), an RNA with nasal secretion. The mouth is also involved, of the Togavirus family that originated from presenting with a diffuse and asymptomatic red Africa, has infected persons in Asia and South appearance. Severe cases may present cervical America and has been reported to give rise to enlargement and high fever, and oral ulceration, gingival inflammation, and oral viral pneumonia is an uncommon but severe com- mucosal pigmentation (Pialoux et al. 2007; plication of the infection. Considering its high Nasci 2014; Scully and Samaranayake 2016). A transmissibility, dental practices may become a detailed discussion of each of these infections is place of spreading the disease, so good clinical beyond the scope of this chapter, but they are practice should include avoiding regular care of reminders that infection is ever changing and infected individuals, and urgent dental attention that all health care workers should attempt to should be provided under rigorous biosafety mea- maintain an understanding of how infection may sures. On the other hand, dental units have an impact upon the clinical care of patients. important role in disseminating health-related information to patients outside the realm of oral health (Glick 2009). Conclusions and Future Directions

Viral infections are common causes of oral illness Emerging Viral Infections that can affect persons of all ages. Common infec- tions such as herpes simplex and coxsackie Just as the incidence of some infections has or will viruses usually give rise to nonlife threatening lessen as a consequence of vaccines and antiviral acute illness, often localized to the mouth. How- therapies, so new viral infections will continue to ever, immunosuppression can greatly increase the emerge, some of which can have implications for risk of severe orofacial viral infection (e.g., vari- oral health and/or oral health care. Similarly, some cella zoster) and possibly life changing (e.g., infections that were previously localized to certain CMV retinitis) or fatal disease (e.g., HHV-8 asso- geographical regions will spread across the globe ciated Kaposi’s sarcoma). Prompt recognition of as a consequence of migration and/or travel. For the clinical features of possible viral infection can example, the Ebola virus, an RNA filovirus easily greatly reduce disease morbidity or mortality. transmitted nonsexually, principally infected per- The risk of some viral infections may be sons from certain African countries but there have influenced by ethnicity and/or socioeconomic Oral and Maxillofacial Viral Infections 23 status (e.g., MEH), lifestyle factors such as ▶ Pharmacotherapeutic Approaches in Oral injecting drug use (e.g., HCV and HIV disease) Medicine or sexual activity (e.g., HPV, HIV, and perhaps ▶ Salivary Gland Disorders and Diseases HCV) and immunocompetency hence a review of ▶ White and Red Lesions of the Oral Mucosa the social and medical histories of people with suspected viral infection can be sometimes diag- nostically helpful. The treatment of viral infec- References tions continues to improve thanks to the availability of a widening range of antiviral Anjos KS, Ferreira MME, Arruda MC, Ramos KS, agents, although over prescribing of such agents Magalhães AP. Epidemiological characterization of varicella cases in patients of a university hospital will undoubtedly increase the spread emergence located in Recife. Rev Bras Epidemiol. 2009;12(4): and spread of antiviral resistant infections. Simi- 523–32. larly, while vaccines for viral infections continue Arduino PG, Porter SR. Herpes simplex virus type 1 infec- to become available (e.g., varicella zoster and tion: overview on relevant clinico-pathological fea- tures. J Oral Pathol Med. 2008;37(2):107–21. oncogenic types of HPV) there remains no vac- Aswathyraj S, Arunkumar G, Alidjinou EK, Hober D. cines for HIV or HCV and any fall in publicly Hand, foot and mouth disease (HFMD): emerging epi- funded immunization programs can lead to the demiology and the need for a vaccine strategy. Med – re-emergence of life-threatening (preventable) Microbiol Immunol. 2016;205:397 407. Beder Ribeiro CM, Ferrer I, Santos de Farias AB, infections (e.g., mumps). Lastly, several emerging Fonseca DD, Morais Silva IH, Monteiro Gueiros LA, viral diseases represent a significant public health Carvalho AT, Porter SR, Leao JC. Oral and genital HPV problem in several countries, and oral involve- genotypic concordance between sexual partners. Clin – ment is yet not adequately recognized. There is Oral Investig. 2014;18(1):261 8. Burger-Calderon R, Webster-Cyriaque J. Human BK ongoing research aiming to determine if a less polyomavirus-the potential for head and neck malig- intense treatment is an adequate strategy for nancy and disease. Cancers (Basel). 2015;7(3): HPV+ . However, the man- 1244–70. agement strategies for viral infections in severely Cannon MJ, Davis KF. Washing our hands of the congen- ital cytomegalovirus disease epidemic. BMC Public immunosuppressed individuals should also be a Health. 2005;5:70. focus of clinical training and research efforts. Clarkson E, Mashkoor F, Abdulateef S. Oral viral infec- tions. Diagn Manag Dent Clin N Am. 2017;61:351–63. Cohen JI. Epstein–Barr virus infection. N Engl J Med. 2000;343:481–92. Cross-References Cunningham AL, Diefenbach RJ, Miranda-Sakesena M. The cycle of human herpes simplex virus infection: ▶ Clinical Evaluation of Oral Diseases virus transport and immune control. J Infect Dis. – ▶ Clinical Immunology in Diagnoses of Maxillo- 2006;194(1):11 8. Elad S, Zadik Y, Hewson I, Hovan A, Correa ME, facial Disease Logan R, Elting LS, Spijkervet FK, Brennan MT. A ▶ Cutaneous Pathology of the Head and Neck systematic review of viral infections associated with Region oral involvement in cancer patients: a spotlight on ▶ Herpesviridea. Support Care Cancer. 2010;18(8): Head and Neck Tumors – ▶ 993 1006. Laboratory Medicine and Diagnostic Pathology Fatahzadeh M, Schwartz RA. Human herpes simplex ▶ Non-Odontogenic Bone Pathology labialis. Clin Exp Dermatol. 2007;32(6):625–30. ▶ Oral and Maxillofacial Fungal Infections Fatahzadeh M, Schwartz RA. Oral Kaposi’s sarcoma: a – ▶ Oral Lichen Planus review and update. Int J Dermatol. 2013;52:666 72. ▶ Ficarra G. Oral ulcers in HIV-infected patients: an update Oral Manifestations of Systemic Diseases and on epidemiology and diagnosis. Oral Dis. 1997;3 Their Treatments (Suppl 1):S183–9. ▶ Oral Mucosal Malignancies Ghrenassia E, Martis N, Boyer J, Burel-Vandenbos F, fi ▶ Oral Ulcerative Lesions Mekinian A, Coppo P. The diffuse in ltrative lympho- ▶ cytosis syndrome (DILS). A comprehensive review. Oral Vesicular and Bullous Lesions J Autoimmun. 2015;59:19–25. ▶ Pediatric Oral Medicine 24 S. Porter et al.

Glick M. Do dentists have a role in fighting the latest H1N1 Patel N, Snyder LD, Finlen-Copeland A, Palmer SM. pandemic? J Am Dent Assoc. 2009;140:1072–4. Is prevention the best treatment? CMVafter lung trans- Grahn A, Studahl M. Varicella-zoster virus infections of plantation. Am J Transplant. 2012;12:539–44. the central nervous system – prognosis, diagnostics and Patton LL. Current strategies for prevention of oral mani- treatment. J Infect. 2015;71(3):281–93. festations of human immunodeficiency virus. Oral Surg Ioos S, Mallet HP, Leparc Goffart I, Gauthier V, Cardoso T, Oral Med Oral Pathol Oral Radiol. 2016;121(1):29–38. Herida M. Current Zika virus epidemiology and recent Patton LL, Ramirez-Amador V, Anaya-Saavedra G, epidemics. Med Mal Infect. 2014;44:302–7. Nittayananta W, Carrozzo M, Ranganathan K. Urban Ko HM, Hernandez-Prera JC, Zhu H, Dikman SH, legends series: oral manifestations of HIV infection. Sidhu HK, Ward SC, Thung SN. Morphologic features Oral Dis. 2013;19:533–50. of extrahepatic manifestations of hepatitis C virus Pialoux G, et al. Chikungunya, an epidemic arbovirosis. infection. Clin Dev Immunol. 2012;2012:1. 740138 Lancet Infect Dis. 2007;7(5):319–27. Korostil IA, Regan DG. Varicella-zoster virus in Perth, Pinheiro R, França TT, Ribeiro CM, Leão JC, de Souza IP, Western Australia: seasonality and reactivation. PLoS Castro GF. Oral manifestations in human immunodefi- One. 2016;11(3):1–13. ciency virus infected children in highly active antire- Lê MP, Stitou H, Soulie C, Katlama C, Peytavin G. troviral therapy era. J Oral Pathol Med. 2009;38(8): Sialolithiasis in an HIV-1-infected patient treated 613–22. with atazanavir/ritonavir monotherapy. J Antimicrob Pinheiro R, de França TR, Ferreira D de C, Ribeiro CM, Chemother. 2013;68(3):727–9. Leão JC, Castro GF. Human papillomavirus in the oral Leão JC, Caterino-De-Araújo A, Porter SR, Scully C. cavity of children. J Oral Pathol Med. 2011;40(2): Human herpesvirus 8 (HHV-8) and the 121–6. etiopathogenesis of Kaposi’s sarcoma. Rev Hosp Clin Portella AVT, Souza LCB, Gomens JMA. Herpes-zoster Fac Med Sao Paulo. 2002;57:175–86. and post-herpetic neuralgia. Rev Dor. 2013;14(3): Leão JC, Gueiros LA, Lodi G, Robinson NA, Scully C. 210–5. Zika virus: oral healthcare implications. Oral Dis. Puenpa J, Mauleekoonphairoj J, Linsuwanon P, 2017;23:12–7. Suwannakarn K, Chieochansin T, Korkong S, Lopes MA, de Souza Filho FJ, Jorge Júnior J, Theamboonlers A, Poovorawan Y. Prevalence and de Almeida OP. Herpes zoster infection as a differential characterization of enterovirus infections among pedi- diagnosis of acute . J Endod. 1998;24:143–4. atric patients with hand foot mouth disease, herpangina Luzuriaga K, Sullivan JL. Infectious mononucleosis. and influenza like illness in Thailand, 2012. PLoS One. N Engl J Med. 2010;362(21):1993–2000. 2014;9(6):e98888. Mainville GN, Marsh WL, Allen CM. Oral ulceration Rath IB, Beltrame AP, Carvalho AP, Schaeffer MB, associated with concurrent herpes simplex virus, cyto- Almeida IC. HIV-associated salivary gland disease– megalovirus, and Epstein-Barr virus infection in an clinical or imaging diagnosis? Int J Paediatr Dent. immunocompromised patient. Oral Surg Oral Med 2015;25(4):233–8. Oral Pathol Oral Radiol. 2015;119:e306–14. Said AK, Leao JC, Fedele S, Porter SR. Focal epithelial Mazul AL, Taylor JM, Divaris K, Weissler MC, Brennan P, hyperplasia – an update. J Oral Pathol Med. Anantharaman D, Abedi-Ardekani B, Olshan AF, 2013;42(6):435–42. Zevallos JP. Oral health and human papillomavirus- Sauerbrei A. Diagnosis, antiviral therapy, and prophylaxis associated head and neck squamous cell carcinoma. of varicella-zoster virus infections. Eur J Clin Micro- Cancer. 2017;123(1):71–80. biol Infect Dis. 2016;35(5):723–34. Mell HK. Management of oral and in the Schiödt M, Dodd CL, Greenspan D, Daniels TE, emergency department. Emerg Med Clin North Am. Chernof D, Hollander H, Wara D, Greenspan JS. Nat- 2008;26:457–73. ural history of HIV-associated salivary gland disease. Nasci RS. Movement of chikungunya virus into the west- Oral Surg Oral Med Oral Pathol. 1992;74:326–31. ern hemisphere. Emerg Infect Dis. 2014;20:1394–5. Schneider JW, Dittmer DP. Diagnosis and treatment of Northfield JW, Harcourt G, Lucas M, Klenerman P. Immu- Kaposi sarcoma. Am J Clin Dermatol. 2017;18:529. nology of viral co-infections with HIV. Arch Immunol in press Ther Exp. 2005;53(1):3–12. Scott LA, Stone MS. Viral . Dermatol Online J. Odumade OA, Hogquist KA, Balfour HH Jr. Progress 2003;9:4. and problems in understanding and managing primary Scully C, Samaranayake LP. Emerging and changing Epstein-Barr virus infections. Clin Microbiol Rev. viral diseases in the new millennium. Oral Dis. 2011;24(1):193–209. 2016;22(3):171–9. Oliveira JL, Freitas RT, Arcuri LJ, Gomes AP. Epstein-Barr Sedghizadeh PP, Billington WD, Paxton D, Ebeed R, virus and infectious mononucleosis. Rev Bras Clin Mahabady S, Clark GT, Enciso R. Is p16-positive oro- Med. 2012;10(6):535–43. pharyngeal squamous cell carcinoma associated with Padayachee A, van Wyk CW. Human papillomavirus favorable prognosis? A systematic review and meta- (HPV) DNA in focal epithelial hyperplasia by in situ analysis. Oral Oncol. 2016;54:15–27. hybridization. J Oral Pathol Med. 1991;20:210–4. Oral and Maxillofacial Viral Infections 25

Sheikh V,Caplan M, Wilson EM, Papadi B, Rosenberg AZ, Syebele K. Regression of both and parotid Higgins J, Driscoll B, Filie AC, Sereti I. Cytomegalo- swellings, following antiretroviral therapy. Int J Pediatr virus immune reconstitution inflammatory syndrome Otorhinolaryngol. 2010;74(1):89–92. manifesting as sialadenitis in an HIV-infected patient. Torres R, Cottrell D, Reebye UN. Ulcerative tongue lesion AIDS. 2013;27(11):1833–5. secondary to cytomegalovirus. J Mass Dent Soc. Sherman AC, Sherman KE. Extrahepatic manifestations 2004;53(3):36–7. of hepatitis C infection: navigating CHASM. Curr Tyor W, Harrison T. Mumps and rubella. Handb Clin HIV/AIDS Rep. 2015;12(3):353–61. Neurol. 2014;123:591–600. Shin JU, Oh SH, Lee JH. A case of hand-foot-mouth Werner RN, Nikkels AF, Marinović B, Schäfer M, disease in an immunocompetent adult. Ann Dermatol. Czarnecka-Operacz M, Agius AM, Bata-Csörgő Z, 2010;22(2):216–8. Breuer J, Girolomoni G, Gross GE, Langan S, Lapid- Solomon T, Lewthwaite P, Perera D, Cardosa MJ, Gortzak R, Lesser TH, Pleyer U, Sellner J, Verjans GM, McMinn P, Ooi MH. Virology, epidemiology, patho- Wutzler P, Dressler C, Erdmann R, Rosumeck S, genesis, and control of enterovirus 71. Lancet Infect Nast A. European consensus-based (S2k) guideline on Dis. 2010;10:778–90. the Management of Herpes Zoster – guided by the SteelFisher GK, Blendon RJ, Bekheit MM, Lubell K. The European dermatology forum (EDF) in cooperation public’s response to the 2009 H1N1 influenza pan- with the European academy of dermatology and demic. N Engl J Med. 2010;362:e65. venereology (EADV), Part 2: treatment. J Eur Acad Steigman AJ, Lipton MM, Braspennickx H. Acute Dermatol Venereol. 2016;31:20. https://doi.org/10.11 lymphonodular pharyngitis: a newly described condi- 11/jdv.13957. tion due to . J Pediatr. Wilson KF, Meier JD, Ward PD. Salivary gland disorders. 1962;61:331–6. Am Fam Physician. 2014;89(11):882–8. Stojanov IJ, Woo SB. Human papillomavirus and Epstein- Barr virus associated conditions of the oral mucosa. Semin Diagn Pathol. 2015;32(1):3–11.