Viral, fungal infections MUDr. Víta Žampachová I. ÚP Viral infections - herpesviruses nHSV-1, HSV-2: herpetic stomatitis nVaricella-zoster (VZV, HHV-3): chickenpox, shingles nEBV (HHV-4): inf. mononucleosis, hairy leukoplakia, ML nCMV (HHV-5): lesions in immunodeficient p. nHHV-6: roseola infantum, mononucleosis sy nHHV-7: roseola infantum?, mononucleosis sy? nHHV-8: Kaposi sarcoma, effusion lymphoma n n n Viral infections – other viruses nEnteroviruses – Coxsackie A: herpangina; hand-foot-and-mouth disease; acute lymphonodular pharyngitis nParamyxoviruses – rubeola (measles) n mumps (parotitis) nOrthomyxoviruses - influenza nTogavirus – rubella (German measles) nHPV – viral warts (papilloma), dysplasia, ca nHIV - AIDS n n Herpetic lesions copy Herpes simplex virus nMucocutaneous infection, retrograde infection along sensory nerves, latent infection in cranial nerve or dorsal spinal ganglia, mucocutaneous recurrences nHSV-1 - Mostly orolabial (cold sores, fever blisters) - 20-50% of initial genital herpes nHSV-2 - Mostly genital; oral infection with ↑ rate - >90% of recurrent genital herpes HSV – primary infection ndirect contact or droplet spread nmay be asymptomatic npharyngotonsillitis possible, mostly in adults nprimary herpetic gingivostomatitis – children 6 months – 5 years nabrupt onset, fever, chills, nausea, lymphadenopathy nmultiple small vesicles on oral mucosa → ulceration → erythematous mucosa nsatellite vesicles on perioral skin (saliva) n n HSV – primary infection File0278 copy HSV infects neurons that innervate the epithelial tissue The virus travels along the neuron (retrograde transport on sensory nerves) oral mucosa → trigeminal ganglia genital mucosa → sacral ganglia Blockage of viral DNA transcription → latent infection. ↓of host immunity – dysbalance - reactivation HSV - latency copy HSV - reactivation Several agents may trigger recurrence: stress, fatigue, menstruation, pregnancy exposure to strong sunlight, local trauma fever – respiratory or GIT infection Recurrent infection – at the primary site or near area (same involved ganlion).Vesicles with infectious virus formed on the mucosa → spread. Recurrent infection usually less pronounced than the primary infection (without systemic signs) and resolves more rapidly The virus replicates in the epithelial tissue → characteristic „fever blister“ or „cold sore“. The blister ulcerates → crusted lesion → healing without scar formation HSV- pathology copy Herpes simplex nImmunocompromised patients - lesions may occur throughout the mouth. nHerpetic ulcer persisting >1 month without known immunosuppression - indicator of possible AIDS. nHerpetic whitlow: a crusting ulceration on the fingers or hands, extremely painful. ! working on patients with active HSV Intraoral HSV Linear vesicles → rupture → ulceration copy HSV in immunocompromised 80FF9 Hard palate HSV in AIDS 17_024 Herpes simplex nother localisations: nherpetic keratitis → corneal blindness nherpetic encephalitis nskin herpetic lesions – in damaged skin (trauma, preexisting disease) HIV-HSV-mi HSV Tzanck smear 2FF10 Multinucleated giant cell Varicella - Zoster nVZV primary infection: chickenpox – fever, malaise, headache, rash: vesicle → pustule → ulcer → crust nin oral cavity on buccal mucosa + hard palate, resembles aphthous ulcers, 7-10 days Varicella Zoster – Chicken pox C:\Users\Gleinser\Desktop\Oral Chicken pox.jpg C:\Users\Gleinser\Desktop\Oral Chicken Pox 2.jpg C:\Users\Gleinser\Desktop\Cutaneous chicken pox.jpg C:\Users\Gleinser\Desktop\chickenpox21.jpg Herpes zoster n nDuration of the lesion is dependent on: nAge: young ~ 2-3wks, adults~ 5-6wks nSeverity of lesions nImmunosuppression nIncidence increases with age (esp.>50 yrs) and immunosuppression. nVaccination of older people possible. nSpecific antiviral drugs. Varicella Zoster - Shingles C:\Users\Gleinser\Desktop\Shingles1.jpg C:\Users\Gleinser\Desktop\Shingles.jpg copy VZV - unilaterality 22 65_004 File0285 copy Varicella - Zoster nSecondary infection (Shingles) nLatency within the dorsal root ganglia nRare in the immunocompetent nPresentation: Prodrome of burning or pain over dermatome. Over 1-5 days new lesions, typically along a dermatome with some overflow to adjacent dermatomes. nMaculopapular rash, development similar to primary form (vesicles → crust). Oral lesions typically after skin involvement Trigeminal nerve reactivation • uveitis, keratitis, conjunctivitis Cranial nerve reactivation • Bells palsy: weakening or paralysis of facial muscles, involvment of the 7th cranial nerve, not permanent. • (Ramsay-Hunt syndrome: virus spreading to facial nerves. Characterized by intense ear pain, a rash around the ear, mouth, face, neck, and scalp, and paralysis of facial nerves. Symptoms may include hearing loss, vertigo, and tinnitus.) VZV pathology VZV pathology Post-herpetic neuralgia: chronic burning or itching pain; hyperesthesia (increased sensitivity to touch) Epstein Barr virus nInfectious mononucleosis nGeneral: After 3-7 week incubation period, bilateral enlargement of cervical and other LN, fever, malaise, possible splenomegaly. Pharyngitis with hyperplasia of lymphoid tissue, pseudomembranous tonsillitis. Atypical lymphocytes in the blood. n nCutaneous presentation: edema of eyelids, macular or morbilliform rash. Macular eruption on trunk. n nMucous membranes with 5-20 pinhead sized petechiae at junction of soft and hard palate. (Forsheimer spots). Stomatitis with erythema and ulceration. nSpread by saliva! n Infectious mononucleosis red9 •Palatal petechial bleeding – Forsheimer spots •Necrotizing ulcerative gingivitis during mononucleosis possible, ! diff. dg. copy Forsheimer spots mono_2 Pseudomembranous tonsillitis in inf. mononucleosis Oral hairy leukoplakia nAssociated with chronic shedding of EBV in the oral cavity in profound immunodeficiency. nPresentation: Poorly demarcated, irregular, white plaques on lateral aspect of tongue. nCannot be removed by scraping (x thrush). nIn immunosuppression (esp. AIDS), HIV workup! nDiagnosis: microscopy, in situ hybridization nManagement: diagnosis + immunosuppression treatment Oral hairy leukoplakia hairy%20leukoplakia copy Human herpesvirus 6 and 7 nRoseola infantum (sixth disease) nPresentation: Onset of high fever resolving in about 4 days, followed by a morbilliform erythema of rose colored macules on neck, trunk and buttocks, less commonly on the face and extremities. nLesions may be surrounded by halo. nComplete resolution in 1-2 days. nHHV 6 infection is nearly universal. nHHV 7 similar to 6. May occur later. nIn adults may resemble to mononucleosis. Roseola infantum roseola copy Human herpes virus 8 nHHV-8 associated with Kaposi sarcoma in virtually all cases. nIncludes AIDS, post-transplant, African and Mediterranean cases. nHHV-8 is found in KS lesions, saliva, blood and semen of infected individuals. nAssociated with body cavity based B-cell lymphoma. nLesions on mucosal membranes possible, usually starts on skin. Kaposi‘s sarcoma Kaposi’s sarcoma ind5140 Plump spindled cells outlining vascular spaces copy Enteroviruses – Coxsackie A nherpangina nhand-foot-and-mouth disease; acute lymphonodular pharyngitis nTransmission: fecal-oral n50-80% of infections are asymptomatic nPossible skin rash, mimics other virus infections nCommon cause of meningitis, myocarditis nChildren <10 nSore throat (herpangina) + vesicles; fever; cutaneous lesions including hand and feet (hand, foot and mouth disease) n n Hand, foot and mouth disease herpangina In mouth similar lesions: red macules→ fragile vesicles → ulcerations. Healing in 7-10 days Measles nRubeola nTransmission: direct droplet contact; incidence greater in winter-spring months nIncubation: 2 weeks nRash evolves from face to trunk to extremities (including palms and soles) nFever and the three Cs: cough, coryza and conjunctivitis nKoplik spots: multiple little white-bluish macules on red background, on the oral (buccal) mucosa opposite to the molar teeth; prior to exanthema; epithelial necrosis nIn malnutrition – necrotizing ulcerative stomatitis, noma, candidiasis nin early childhood – odontogenesis affected, enamel hypoplasia Measles nComplications common (20%), in children and young adults: nMalnutrition esp. vitamin A deficiency is a major cause of mortality nComplications include: nOtitis media nPneumonia nEncephalitis (incl. subacute sclerosing panencephalitis) nVaccination n n Rubella nGerman measles, togavirus nTransmission: respiratory droplets nIncubation period: 2-3 weeks nInfections may be sub-clinical esp. in young children nMild to no prodromal phase; nRash (nonspecific, difficult to make a clinical diagnosis) nAdenopathy (swollen lymph nodes) nOral lesions: small dark red papules on soft palate nAdults may also get mild arthritis Rubella on a kids back Rubella on a torso Rubella Rubella nCongenital rubella - the most severe complication nMost infections and complications occur in the first 16 weeks of pregnancy (90% transmission rate to fetus) nInfants are born with numerous defects nCardiac abnormalities nCataracts nDeafness nBrain, liver and organ damage n n • Estimated: 10-30% of oral cancers positive for HPV • Rising tendency in younger patients • Possible gradual decrease due to vaccination •+-70 subtypes documented, high risk types 16, 18; low risk 6, 11 •Vaccination Human papillomavirus Human papilloma viruses nHPV lesions commonly self-limited in immunocompetent people. nLong-standing HPV lesions most commonly in immunocompromised individuals. nDiagnosis based on history, clinical appearance, and biopsy. nCommon in early HIV infection. nSpiky warts, raised, cauliflower-like appearance. Squamous papilloma: • Most common in 30 - 50 yr old • Possible in males and females • HPV-6, 11 in 50% of the lesions • Tongue and soft palate common sites Papilloma lesions of the oral cavity Finger-like projections with fibrovascular core condylomata2, přehled40x condylomata2, 200x.jpg HPV: koilocytic change of epithelia (perinuclear halo, shrinked nucleus) Verruca vulgaris nAttached gingiva nLabial/buccal mucosa Fall 2009 Heidi Emmerling, RDH, PhD DHYG 138 Oral Pathology 47 File0269 File0270 ← → copy Image015 Verruca vulgaris STD associated lesion. Mouth and genitalia. HPV- 6, 11, ... Complete virions produced Condyloma accuminatum (venereal vart) Image067 HPV mild dysplasia, koilocytes Acquired immunodeficiency syndrome (AIDS) §Oral lesions - prominent features of AIDS and HIV infection. §Oral lesions due and according to the rate of loss of T-helper cells. §Early studies: approximately 90% of HIV+ patients will present with at least one oral lesion in the course of their illness. n Current studies report the prevalence or oral lesions has significantly declined (HAART – highly active antiretroviral therapy) n Oral lesions in patients with HIV may be particularly large, painful or aggressive n n n mod2_22 mod3_28 Necrotizing ulcerative periodontitis Aphthous ulcerations [USEMAP] Special importance of oral health in HIV patients copy HIV/AIDS oral-pharyngeal syndromes nInterferes with oral hygiene → more oral+pharyngeal pathology nInterferes with nutritional intake → wasting syndrome HIV treatment compliance may be impacted by oral pain, xerostomia, dysphagia nPsychosocial dimensions Avoidance of social contact due to facial appearance Depressive effects of persistent oral pain Medications n nHIV patients frequently on numerous antiretroviral medications with complex dosing regimens. nNumerous drug-to-drug interactions documented. nComplete list of all medications essential to minimize potential adverse drug interaction to medications that may be prescribed by the dental provider. Lesions strongly assoc. with HIV nCandidiasis – erythematous, hyperplastic, pseudomembranous nHairy leukoplakia (EBV) nHIV-associated periodontal disease – HIV gingivitis, NUG, HIV periodontitis, necrotizing stomatitis nKaposi sarcoma (HHV-8) nNon-Hodgkin malignant lymphoma (EBV) Lesions less assoc. with HIV nAtypical ulceration (oropharyngeal) nIdiopathic thrombocytopenic purpura nSalivary gland lesions – xerostomia, major salivary gland enlargement nOpportunistic viral infections (CMV, HSV, VZV, HPV) nOpportunistic bacterial infections (Mycobacterium avium-intracellulare) nOpportunistic fungal infections (aspergillosis, histoplasmosis) n Lesions possibly assoc. with HIV nBacterial infections other than gingivitis/periodontitis nMelanotic hyperpigmentation nNeurologic disorders (n. facialis palsy, trigeminal neuralgia) nSquamous cell carcinoma (HPV) HIV/AIDS oropharyngeal syndromes – most common nCandidiasis 28%-75% nNecrotizing gingivitis nHSV, CMV, HIV, EBV ulcers nRecurrent aphthous ulcers nDrug-derived ulcers nKaposi sarcoma nDental abscesses n Candidiasis nCandida albicans in immunodeficient patients (HIV, iatrogenic – chemo/radiotherapy, posttransplant, other immunosuppressive therapy) nCommonly chronic multifocal lesions nForms: pseudomembranous n erythematous (palate, tongue ~ median rhomboid n glossitis) n hyperplastic (cheeks) n angular cheilitis Oral-pharyngeal candidiasis candi6 candi4 candi5 candi3 copy copy copy Hairy leukoplakia nPossible early manifestation of AIDS status. nFilamentous white plaque (hyperkeratotic, non-removable) uni-/bilaterally on lateral borders, anterior portion of the tongue. nBorders irregular or jagged in contour, sharply delineated. nPossible on entire dorsal surface of the tongue. On buccal mucosa flat appearance. nMicro: acanthosis, parakeratosis Hairy leukoplakia The surface texture is grainy, rough or „shaggy“ in appearance. scan06b copy Oral hairy leukoplakia HIV-oral-hairy-leuc01 Differential diagnosis nPhysiologic hyperkeratosis. nIdiopathic leukoplakia. nLichen planus. nHyperplastic candidiasis. n HIV-associated periodontal disease nHIV-associated periodontis resembles acute necrotizing ulcerative periodontitis superimposed on rapidly progressive (necrotizing ulcerative) gingivitis, possible progression into necrotizing stomatitis. nOther symptoms include: •Interproximal necrosis and cratering •Marked swelling •Intense erythema over the free and attached gingiva •Intense pain •Spontaneous bleeding and bad breath Atypical periodontal disease in a patient with HIV infection. 17_018a 17_018b HIV-associated gingivitis nLinear gingival erythema: a bright red line along the border of the free gingival margin (atypical gingivitis). nPossible progression over the attached gingival and alveolar mucosa. nNot specific for HIV, possibly due to hyperemia, candidiasis? HIV gingivitis copy Opportunistic infections nImportant for diagnosis and prognosis (type according to the CD4+ T-cell count) nCommon antibiotic/antiviral/antifungal prophylaxis for opportunistic infections nInflammation nMalignancies nKaposi sarcoma (KS – HHV-8) nNon-Hodgkin lymphoma (NHL - EBV) nSquamous cell carcinoma (SCC – HPV) n n n n Kaposi sarcoma nKaposi sarcoma: HHV-8 opportunistic infection in immunodeficiency nVascular – endothelial sarcoma nSolitary or multiple bluish, blackish, or reddish macules – elevated lesions - ulcerations. nKaposi sarcoma is one of the intraoral AIDS– defining lesions. n HIV-Kaposi-ma102 Kaposi sarcoma 17_023 HIV cervical lymphadenopathy n nEnlargement of the cervical (neck) nodes. nLymphadenopathy frequently seen in association with HIV – PGL – persistent generalized lymphadenopathy nDiff. dg. x ML, metastasis HIV cervical lymphadenopathy 17_019 HIV lymphoma nSolitary lump or nodule, swelling, or nonhealing ulcer anywhere in the oral cavity. nThe swelling possibly ulcerated or covered with intact, normal-appearing mucosa. nUsually painful, the lesion grows rapidly in size, may be the first evidence of lymphoma. nCommon association with EBV nSeveral histopathologic types, atypical localization Fig. 17-21 HIV lymphoma. 17_021 HIV lymphoma HIV-ML-brain Primary malignant lymphoma (brain) HPV lesion on the lip of a patient with AIDS. 17_025 Fungal infections nCandidiasis: nHistoplasmosis nBlastomycosis nCryptococcosis nAspergillosis n... n Candida albicans and other Candida species nHarmless inhabitants of the skin and mucous membranes of all humans nNormal immune system keeps candida on body surfaces - skin and mucous membranes integrity nPresence of normal bacterial flora nOpportunistic infection 9 The most important risk factors nNeutropenia, anaemia (acquired in leukemia, radio/chemotherapy, …) nDiabetes mellitus nAIDS nSCID + other inborn immunodeficiencies (myeloperoxidase defects) nBroad-spectrum antibiotics, steroids nLocal factors – trauma incl. chronic (denture), hygiene, smoking, carbohydrate diet, xerostomia The most important risk factors nIndwelling catethers nMajor surgery nOrgan transplantation nAge dependent – neonates, very old nSeverity of any illness nIntravenous drug addicts nPoor nutritional status Candidiasis nConfirmation with KOH smear, tissue PAS or silver stains nTreatment - topical or systemic nPrimary problem treatment Candidiasis nSymptoms: burning, dysgeusia, sensitivity, generalized discomfort nAngular cheilitis, coinfection with staph. may be present nAcute - atrophic red patches or white plaque-like surface colonies. nChronic - denture related form confined to area of appliance n n Candidiasis nAcute (and chronic in immunocompromised) nPseudomembraneous („Thrush“) - white nDOES scrape off nAtrophic („Erythematous“) - red n(Does NOT scrape off) nChronic nHyperplastic („Candidal leukoplakia“) - white n(Does NOT scrape off) Candidiasis nCandida-associated primary oral lesions n Denture stomatitis n Angular cheilitis n Median rhomboid glossitis nSecondary oral lesions in generalized candidiasis n Systemic mucocutaneous c. n Candidiasis: Acute pseudomembraneous nWhite thick lesion - trush nUnderlying tissue: erythematous, haemorrhagic, pruritic nSuperficial necrosis + hyphae + yeast forms, infl. infiltrate – mostly neutrophils nNewborns, old debilitated p., p. with risk factors Thrush/ Candidiasis C:\Users\Gleinser\Desktop\Oral Thrush.JPG copy Candidiasis n candidiasis1 copy Pseudomembrane with yeasts Erythematous candidiasis. 17_004 Mainly on tongue + palate, in ATB/corticosteroid therapy (ATB sore tongue) – microorganism dysbalance red, painful Candidiasis: Chronic hyperplastic - candidal leukoplakia nKeratotic plaques or papules, white, rough surface (no scraping off), erythematous background, vague borders nHyperkeratosis with acanthosis, oedema, neutrophils + microabscesses, plasma cells + lymphocytes in stroma nSites: labial commissure, labial, buccal vestibule nRisk factors: smoking, poor oral hygiene (dentures), xerostomia nCancer risk: Biopsy mandatory of all speckled erythroplakia or erythroleukoplakia,↑ SCC risk reactive atypia x dysplasia n scan05b copy Candidiasis: Red chronic oral lesions nAngular cheilitis – Perleche (poor oral closure, saliva accumulation) nMedian rhomboid glossitis nDenture stomatitis – atrophic c. on palate Angular cheilitis (Perleche) nLabial commisures, moist fissures nElderly – facial and dental architecture nYouth – thumbsucking, lollipops nThrush in DM II or HIV nMultifactorial: candida associated, Str., Staph., deficiency of iron, riboflavin, vitamin A, E, etc. nErythema, fissuring, pain n PERLECHE2 PERLECHE1 Candidiasis C:\Users\Gleinser\Desktop\Candidal angular chelitis.jpg Angular chelitis copy Median rhomboid glossitis nShiny oval or diamond shaped elevation, midline, directly in front of the circumvallate papillae. Asymptomatic. nCandida species may be present + trauma nMicro: Chronic inflammation with fibrosis with possible hyphae in areas of parakeratosis, loss of papillae n medrhombgloss1 copy Denture stomatitis nTissue trauma – dentures + poor hygiene → secondary c. nPalate: erythema, oedema, symptomless nLocalized – spotty erythema nGeneralized – diffuse erythema nChronic inflammatory papillary hyperplasia – erythema + rough granular surface nMicro: superficial overgrowth, no epithelial invasion by c. n n Hairy tongue nDiffuse elongation of the filiform papillae of the dorsum surface of the tongue nCandida usually present (exfoliative cytology) nSuperficial candidiasis stimulates epithelial n hyperplasia to produce the thickened layer nCoffee, tea, tobacco - secondary staining - black hairy tongue 1366FIGURE_1 Hairy tongue copy copy Chronic mucocutaneous candidiasis nPersistent superficial infection – oral + other mucosae, skin + adnexa nImmunodeficiency, endocrine dysfunction Invasive fungal infections nFungi that commonly cause invasive infection can be divided into two groups: nOpportunistic fungi, (that occur widely) ne.g. Aspergillus spp., Candida spp., Cryptococcus, Zygomycetes nGeographically defined, „dimorphic fungi“ ne.g. Histoplasma capsulatum nCoccidioimycosis Invasive fungal infections nDiagnosis nMicroscopic nSecretions, KOH nHistology nCulture n! may occur as a contaminant nLaboratory (antigenes, PCR) HIV-mycosis-colony01 Fungal colony Invasive candidiasis nUsually begins with candidemia (but in only about 50% of cases candidemia can be proven) nIf phagocytic system normal, invasive infection stops in this stage nProgression – secondary deep visceral candidiasis n Invasive fungal infections nAspergillus spp (esp. A. fumigatus) nEpidemiology nWidespread, grows on rotting vegetation. Spores commonly present in air. Important predisposing factor: immunosuppression nClinical presentations nAllergic bronchopulmonary aspergillosis - Asthma-like symptoms. - Fungus grows in bronchial secretions. nAspergilloma (fungal ball) - develops in cavities (- lungs, sinuses). nInvasive disease - tissue destruction, pneumonia. Invasive aspergillosis Cryptococcus nMostly in immunosuppressed nPrimary infection in the lungs nSecondary dissemination (meninges, skin, bone) nOral lesions possible – nonhealing ulcers nDg. – biopsy – thick mucoid capsule HIV-cryptoc-mening202 Cryptococcal meningitis Histoplasmosis nIn US the most common systemic fungal infection nIn non-immunocompromised: mild, self limited acute lung disease nIn immunosuppressed: chronic; disseminated – incl. oral lesions – ulcers (x ca!, biopsy) nMicro – macrophagic reaction +/- granulomas HIV-histoplasma03 Histoplasmosis Coccidiomycosis nEndemic in Americas nTypes similar to histoplasmosis (acute lung dis. – „valley fever“; chronic pulmonary; disseminated) nPerioral skin lesions possible – papules, abscesses, nodules nDg.: biopsy, culture HIV-coccidiomyc03 Coccidiomycosis HIV-coccidiomyc-Grocott01 Coccidiomycosis nInvasive fungal infection (mucormycosis) nOpportunistic in the debilitated, immunocompromised, or acidotic patient. n nAetiology: n Fungal spores in enviroment n n nClinical types n 1) Rhino-orbito-cerebral n 2) Pulmonary n 3) Gastrointestinal n 4) Cutaneous n 5) Disseminated Zygomycosis 9 copy Zygomycosis nPathogenesis: nSpore inhalation → germination (hyphae) → local invasion→ nasal mucosa, paranasal sinus, palate, lung n nSpread: n- direct extension n- blood vessel invasion → to the orbit and intracranial → ischemia, necrosis, gangrene and brain abscess Clinical presentation nFever, facial pain or headache, nasal discharge, epistaxis, visual disturbances, and lethargy n n n n n n 2601face DSC02979 DSC05891 copy copy copy n nDiagnosis: requires a high index of suspicion→ risk factors + evidence of tissue invasion n nBiopsy: using fungal stain → broad nonseptate hyphae with right-angle branches n nImaging: X-ray, CT-MRI. 2602biopsy 2603headCT Zygomycosis copy