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Clinical Syndromes Associated with Papillomaviruses Unique Properties of Papovaviruses There is a small icosahedral capsid virion. Double-stranded circular DNA genome is replicated and assembled in the nucleus. These are two major genera: o Papilloma: HPV types 1 to 58+ (as determined by genotype; types defined by DNA homology, tissue tropism, and association with oncogenesis) o Polyoma: SV-40, JC virus, and BK virus Viruses have defined tissue tropisms determined by receptor interactions and the transcriptional machinery of the cell Viruses encode proteins that promote cell growth by binding to the cellular growth-suppressor proteins p53 and p105RB. Polyoma T antigen binds to p105RB and p53. E6 binds to p53, and E7 binds to p105RB. Viruses can cause lytic infections in permissive cells but cause abortive, persistent, or latent infections or immortalize (transform) nonpermissive cells. Disease Mechanisms of Papovaviruses
HPV TYPES SYNDROME SKIN WARTS COMMON UNCOMMON
Plantar wart Common wart Flat wart Epidermodysplasia verruciformis
BENIGN HEAD AND NECK TUMORS
1 2,4 3,10 5,8,17,20,36
2,4 1,7,26,29 27,28,41 9,12,14,15,19,2125,38,46 2,16 -
Laryngeal papilloma Oral papilloma Conjunctival papilloma
6,11 6,11 11
Condyloma acuminatum Cervical intraepithelial neoplasia, cancer
Verruca vulgaris. Common warts are typically single or multiple, flesh colored, dome-shaped papules with a rough, verrucous surface. They can occur anywhere on the skin but are most common on exposed surfaces such as the fingers, hands, feet and face.
Common warts with thrombosed vessels (black dot) on the surface.
Verruca plantaris. Plantar warts occur on weight bearing areas of the feet and commonly exhibit overlying hyperkeratosis. Note the punctuate dark brown dots which represent vessel thrombosed in the superficial dermis. Verruca lanta. Flat warts occur primarily on the face and extremities. They are generally small, flesh or brown-colored, broad based papules varying in number. Autoinoculation from trauma, such as shaving, is a common means of viral spread.
Epidemiology of Papovaviruses
Condyloma acuminate. It is characterized by soft, fleshcolored polypoid or acuminate warts that occur in the anogenital region. It can be extensive and cause pain, itching and bleeding.
Laboratory Diagnosis of Papilloma Infections
Disease Mechanisms of Adenoviruses
DNA probe analysis of an HPV-6-induced anogenital condyloma Dark staining is seen over nuclei of koilocytic cells.
Mechanism of spread of polyomaviruses within the body.
Time Course of Adenovirus Respiratory Infection
Laboratory Diagnosis of Polyomavirus (JC and BK Infections) TEST DETECTS
Pap smear of urinary epithelial cells Electron microscopy Immunofluorescence and immunoperoxidase staining DNA probe analysis Nucleic acid hybridization in clinical specimens Cell culture Human diploid lung fibroblasts Primary human fetal glial cells ADENOVIRIDAE Unique Features of Adenoviruses
Viral inclusions Virions Viral antigens Viral nucleic acids BK and JC viruses Nucleic acids Virus isolation-BK Virus isolation-JC Epidemiology of Adenovirus
Illness Associated with Adenoviruses
ILLNESS CATEGORY MOST COMMON SEROTYPES
Disease Mechanisms of B19 Parvovirus Mechanism of Spread of parvovirus within the body
Endemic respiratory disease Acute respiratory disease of military recruits Adenoviral pneumonia Epidemic keratoconjunctivitis Pharyngoconjunctival fever Less common syndromes Pertussis syndrome Acute hemorrhagic cystitis Hepatic disorders Gastroenteritis Intussusception Musculoskeletal disorders Genital infections Skin infections Infections in immunocompromised hosts
1,2,5 3,4,7,14,21 3,4,7b,14,21 8,19 3,7 1,2,3,5 1,4,7,11,21 3,7 9,12,13,18,25-29, 40-42 1,2,5 7 19 2,4,7,21 32,34-36
Adenovirus conjunctivitis. Adenoviral exanthems are frequently generalized and nonspecific. Other associated findings include fever, rhinitis, pharyngitis, adenopathy and conjunctivitis.
Time course of parvovirus (B19) infection. B19 causes biphasic disease: first, an initial, lytic infection phase characterized by febrile, influenza-like symptoms and then a noninfectious immunological phase characterized by a rash and arthralgia. (Insert time course picture)
Epidemiology of B19 Parvovirus Infections
Hematoxylin and eosinstained sample of adenovirus. Pneumonia, showing inflammation, necrosis and exudates.
PARVOVIRIDAE Unique Properties of Parvoviruses
A slapped-cheek appearance is typical of the rash for erythema infectiosum.
Erythema infectiousum. The third stage of Fifth’s disease begins as the rash starts to fade with areas of central clearing. This leaves a reticulated or lacy pattern of erythema which can last several weeks. The most common complication is join involvement ranging from mild arthralgias to overt arthritis.
NONENVELOPED DNA VIRUSES HUMAN HERPESVIRUSES Properties Distinguishing the Herpesviruses
Unique Features of Herpesviruses
Epidemiology of HSV Infection
HERPES SIMPLEX VIRUS 1 AND 2 Disease Mechanisms for Herpes Simplex Virus
Clinical course of genital herpes infection. The time course and symptoms of primary and recurrent genital infection w/ HSV-2 are compared.
Disease syndromes of HSV. HSV-1 and HSV-2 can infect the same tissue and cause similar diseases but have a predilection for the sites and diseases indicated.
Primary herpes gingivostomatitis is the most common herpes simplex virus-1 infection in children. Vesicles, erythema and swelling occur in the oral cavity and on the lips. Erosion of vesicles leave small shallow ulcers on an erythematous base.
FDA-Approved Antiviral Treatments for Herpesvirus Infections
HERPES SIMPLEX VIRUS 1 AND 2
Acyclovir Adenosine Arabinoside Iododeoxyuridine Trifluridine
Cold sore of recurrent herpes labialis.
Acyclovir Varicella-zoster immune globulin (VZIG) Zoster immune plasma
EBV Herpatic whitlow is characterized by inoculation of the HSV virus into the skin of one or more fingers causing painful superficial or deep vesicles or bullae with a whitish blue-hue. Herpetic coneal ulcer. Corneal infection due to HSV is characterized by dendritic ulcers which are branching morphologic appearance of the lesions. Recurrent infections can lead to scarring and impairment of vision.
*ALSO INHIBITIS HSV AND VZV
VARICELLA-ZOSTER VIRUS Disease Mechanisms of VZV
Eczema herpticum (Kaposi’s varicelliform eruption). Note the vesicles, superficial ulcers and crusts in the antecubital fossa of this toddler with atopic dermatitia.
Genital Herpes. It begins as vesicles or pustules which progress to erosions and ulcers, generally lasting 1-3 weeks. Associated local symptoms for both primary and recurrent genital HSV infections include severe pain, itching, dysuria, inguinal adenopathy and urethral or vaginal discharge. Neonatl herpes. Newborns may acquire primary herpes simplex virus (HSV) infection in utero, during delivery or postnatally. Cutaneous involvement may be minimal or extensive and is not necessarily indicative of the severity of concurrent systemic disease.
Mechanism of spread of VZV within the body
Laboratory Diagnosis of HSV infections
Time course of varicella (chickenpox)
Tzanck stain of herpetic vesicle. Note the large multinucleated giant cell. The preparation is obtained by scraping the base of a new, freshly opened vesicle and staining with Giemsa stain or toluidine blue.
Epidemiology of VZV Infection
Acute herpes zoster. After primary varicellazoster virus infection, the virus persists in a latent form and can be reactivated, resulting in herpes zoster or “shingles”. Herpes zoster is characterized by papules, vesicles and pustules on an inflammatory base in a dermatomal distribution, frequently associated with burning pain and tenderness.
Varicella. After an incubation period of approximately 14-16 days the disease begins with low grade fever, malaise and the appearance of a characteristic generalized pruritic vesicular Eruption (“dewdrop on a rose petal”). Tzanck stain of the contents of a varicella vesicle. Note the multinucleated giant cells. These represent swollen epidermal cells containing intercytoplasmic viral inclusion.
Characteristic skin rash of varicella demonstrating all of the stages of evolution of the rash.
EPSTEIN-BARR VIRUS Disease Mechanisms of Epstein-Barr Virus
Varicella in a child. The eruption generally begins on the trunk or head and spreads centrifugally. New lesions generally begin to crust within 1-2 days. It is common to find various-sized papules, vesicles, pustules and crusts all present on the skin at the same time. Varicella in an adult. Over 90% of primary varicella infections occur in children. In adolescents, adults and immunocompromised patients, the disease can be more severe. Secondary bacterial skin infections, otitis media, pneumonia, encephalitis, hepatitis and Reye’s syndrome are well known complications of varicella infection.
Pathogenesis of EBV. EBV is acquired by close contact between persons
through saliva and infects the B cells. The resolution of the EBV infection and many of the symptoms of infectious mononucleosis result from the activation of T cells in response to the infection.
Differences between Chickenpox and Smallpox
Distribution Chickenpox Relative density centripetal. is Smallpox Relative centrifugal density is
Mode Evolution Time evolution Lesions
Predominance on flexor surfaces and flexures Lesions appear in crops Rapid Superficial Ova or totally irregular Unilocular Scarring superficial slight and
Predominance on extensor surfaces and prominences Lesions progress from stage to stage synchronously Relatively slow Deep set Tend to be circular and regular Vesicles multilocular Scarring severe and deep
Cellular Antigens Associated with EBV-Infected Cells
NAME EBV nuclear antigen ABB. EBNA CHAR. Nuclear BIO. ASSOC. EBNA is a nonstructural antigen and is the first antigent to appear; EBNA is seen in all infected transformed cells, and it binds to cell DNA. EA-R appears before EA-D; its appearace is the first sign that an infected cell has entered lytic cycle. CLIN. ASSOC. Anti-EBNA develops late in infection.
Serological Profile for EBV Infections
Anti-EA-R seen Burkitt’s lymphoma.
Diffuse in cytoplasm and nucleus Cytoplasmic
Viral capsid antigen
Lymphocytedefined membrane antigen
Membrane antigen Heterophile antibody
Cell surface Recognition of PulBunnell antigen on sheep, horse, or bovine erythrocytes
VCA is a late antigen; it is found in virus producer cells. LYDMA is not found on Burkitt’s lymphoma cells; iti s found on cells infected in vitro, and is found on nonproducer cells MAs are the envelope glycoproteins EBV-induced B-cell proliferation promotes production of heterophile antibody.
Anti-EA-D is seen in infectious mononucleosis. Anti-VCA IgM is transient; antiVCA IgG is persistent. LYDMA is not detectable by antibody.
Same as VCA. Early symptoms occur in more than 50% of patients.
Clinical course of infectious mononucleosis and laboratory findings of those with infection. EBV infection may be asymptomatic or produce the symptoms of mononucleosis. The incubation period can last as long as 2 months. Papular acrodermatitis of childhood GianoltiCrosti disease) – a distinctive erythematous, discrete popular eruption that is acrally located with relative sparing of the trunk. Associated findings may include lymphadenopathy, hepatomegaly and
Epidemiology of Epstein-Barr Virus Infection
evidence of hepatitis. Ampicillin rash in a patient with infectious mononucleosis when antibiotics (usually ampicillin) are administered during primary EBV infection, a red or copper colored morbilliform eruption may appear. The rash begins on the trunk and gradually spreads over the entire body.
Hairy leukoplakia caused by EBV.
Lymphoid system Major Organs Neonates
Mononucleosis syndrome, posttransfusion syndrome Carditis, hepatitis Deafness, mental retardation
Leukopenia, lymphocytosis Hepatitis -
Atypical T-lymphocyte (Downey cells) characteristic of infectious mononucleosis.
CYTOMEGALOVIRUS Disease Mechanisms of CMV
Congenital cytomegalovirus (CMV) infection. Cutaneous rash is unusual in acquired CMV infections but is common in congenital CMV infections. Congenital CMV may range from asymptomatic to profound with systemic manifestations including intrauterine growth retardation, hepatosplenomegaly, pneumonia, neonatial jaundice, thrombocytopenia, central nervous system involvement and chrioretinits. Skin findings include purpuric paules and nodules.
Clinical course of CMV infection
Epidemiology of Cytomegalovirus Infection
Laboratory Tests for Diagnosis of CMV infection
CMV-inefcted cell with basophilic nuclear inclusion body.
Roseola infantum or exanthum subitum is a common exanthema of childhood caused by infection with human herpesvirus 6. It is characterized by a febrile illness with mild constitutional symptoms lasting 3-5 days. After rapid defervescence, a pink macular or maclopapular rash appears primarily on the trunk and lasting hours to days.
TISSUE Predominant nature of disease Eyes Lungs Gastrointestinal tract Nervous system CHILDREN/ADULTS Inapparent infection (prominent presentation of disease Polyneuritis, myelitis IMMUNOSUPPRESSED PATIENTS Disseminated disease, severe disease Chorioretinitis Pneumonia Esophagitis, colitis Meningitis and encephalitis, myelitis
POXVIRIDAE Unique Properties of Poxviruses
Properties of Smallpox that Led to Its eradication
Disease Mechanisms of Poxvirus
Diseases Associated with Poxviruses
Spread of Smallpox within the body.
Discrete vesiculopustular stage of smallpox. Smallpox (variola) is a highly contagious disease cuased by Poxvirus variolae, which apparently has been eradicated from the world.
Molluscum contagiosum is a common, benign viral infection of the skin and mucous membranes characterized by distinct single or multiple dome-shaped papule which are flesh or pink colored. Central umbilication can occur.
The virus enters and replicates in the respiratory tract without causing symptoms or contagion. The virus infects macrophages, which enter the lymphatic system and carry the virus to regional lymph nodes. The virus then replicates and initiates a viremia, causing the infection to spread to the skin (rash). A secondary viremia causes the development of additional lesions throughout the host, followed by death or recovery with or without sequelae. Recovery was associated with prolonged immunity and lifelong protection.
Time Course of Smallpox Infection
Skin lesion of molluscum contagiosum.
Vaccinia. Three to 5 days after primary inoculation with vaccinia virus. A vesicle forms, followed by a pustule, which increases in size for 9-10 days and then heals
leaving a scar. Severe localized erythema may occur at the injection site. Orf Lesion on finger of taxidermist.
Microscopic view of molluscum contagiosum. Epidermis filled with molluscum bodies. Wright’s stain of the extruded contents of a molluscum papule. Note the blue stained viral inclusions (molluscum bodies) within the cytoplasm of epidermal cells.
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