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- VIRAL - Digestive system - Systemic with skin eruption - Systemic with hematopoietic disorder - Arbovirus and hemorrhagic Dr. Ratirath Samol, MD. - Warty growths Department of Pathology - Central nervous system Faculty of Medicine, Naresuan University

Viral structure Mechanism of viral infection

. Attachment . Penetration . uncoating . Replication and protein production . Morphogenesis and maturation . Release of virus

1 Tissue change caused by viral infection Classification of viral disease

. Cell necrosis . Respiratory system . Cell swelling -Adenovirus, Rhinovirus, , . Inclusion body formation Respiratory syncytial virus . Giant cell formation . Latent viral infection . Digestive system . Oncogenesis - virus, viral , virus (A,B,C,D,E)

Classification of viral disease Classification of viral disease

. Systemic with skin eruption . Warty growths -Measles virus, Rubella virus, Varicella -Human papilloma virus, molluscum zoster virus, 1and 2, virus Coxsackie Virus . Central nervous system . Systemic with hematopoietic disorder -, virus, Arbo viral - , EBV, HIV virus . Arbovirus and hemorrhagic fever -Dengue virus 1-4

2 Rhinovirus

. Picornaviridae . + single strand RNA Respiratory system . Major cause of . More than 100 serotypes . Binding to intercellular molecule-1 (ICAM-1) receptor on epithelial cells of URI . Bradykinin from host response mucous secretion

Rhinovirus Influenza virus

. Clinical feature: . Orthomyxoviruses -rhinorrhea, nasal congestion, . Classify due to soluble (S) of virion: sore throat, cough, fever - subtype A,B,C . Classify due to glycoprotein envelope: . Common : - Hemagglutinin (H) Adult:-sinusitis H Child:-otitis media, lower respiratory - Neuraminidase (N) N symptom (bronchopneumonia) eg.H1N1, H3N2, H5N1

3 Influenza Antigenic Changes Influenza virus

. Antigenic Drift . Minor change, same subtype . Influenza . Caused by point mutations in gene . (Bird flu) . May result in epidemic . Mexico influenza or Swine influenza (2009 influenza) . Antigenic Shift . Major change, new subtype . Caused by exchange of gene segments . May result in pandemic

Influenza

. Self limited infection of upper airway, Mechanism of the but can extending to lower air way Cytokine Storm Evoked by . Destroy mucociliary function followed Influenza virus by secondary bacterial infection

NORMAL TRACHEAL MUCOSA 7 DAYS POST-INFECTION Lycke and Norrby Textbook of Medical 1993

4 Influenza Avian influenza (Bird flu)

. Clinical feature: - Caused by influenza virus type A, H5N1 - rapid onset of fever, myalgia, - disease of bird, chicken, duck , weakness, cough - transmitted to human by direct contact - progressive symptom 3-5 day with affected animals - clinical subside 2 weeks - virus dies from heat (70 ‘c) . Complication: pneumonia, lung hemorrhage, hyaline membrane disease . Killed viral

Avian influenza Mexico influenza

- Disease in animals . Swine influenza or 2009 influenza low pathogenic . Subtype A, H1N1 highly pathogenic . Infected by respiratory system and direct contact to eye (infection between human) - Disease in humans (2-3 days) . Clinical symptom : similar to influenza fever, cough, sore throat, lymphopenia, severe pneumonia, res. failure, dead

5 Mexico influenza Influenza Antivirals

. People who work with poultry and swine, . Use neuraminidase inhibitors are increased risk of zoonotic infection . Oseltamavir: chemoprophylaxis and . In human, mutation of virus and treatment transmitted between human . Zanamavir: treatment only

Respiratory syncytial virus(RSV) Histopathology

. Most common cause of self- limited . Upper respiratory tract respiratory tract infection in young - mucosal hyperemia, swelling with children eg; bronchiolitis, pneumonia predominant infiltration of lymphocytes, . Transmitted by respiratory droplet and monocytes and plasma cells secretion - mucous overproduction causing obstruction of nasal cavity, sinuses and eustachian tube

6 Histopathology Adenovirus

. Lower respiratory tract . - laryngotracheobronchitis: swelling of . Incubation period 6-9 days vocal cord and abundant mucous . Common cause in child : secretion causing obstruction of small air conjunctivitis, URIs, bronchitis, way and atelectasis pharyngitis (exudate), bronchiolitis, - pneumonia: interstitial infiltration of pneumonia, , cystitis, mainly lymphocytes encephalitis . Immunocompromised host:- high risk for severe pneumonia

Mumps virus

. Paramyxovirus family . Cause of mumps with self limited disease Digestive system in 2 weeks . Clinical:- fever, malaise, headache, parotid swelling and pain . Live attenuated vaccine

7 Pathogenesis Mumps

Inhalation of respiratory droplet contains virus . Extrasalivary gland complication: - aseptic meningitis (most common) dendritic cells at respiratory epithelium capture - orchitis virus and drainage to lymph nodes - oophoritis replication in lymph nodes -

hematogeneous spread to parotid glands (parotitis), and other organs (CNS, pancreas, testis)

Histology Histology

. Parotitis: bilateral 75% . Orchitis: - desquamation of ductal epithelial cells - testis edema, lymphocytes infiltration, - interstitium edema with lymphocytes, hemorrhage and plasma cells infiltration - may be infarction  infertility (13%)

8 Viral enteritis and

. Reovirus family . Rotavirus . Most common cause of in . Norwalk virus children < 1 year of age . Corona virus . Clinical :- fever, rhinorrhea, , abdominal pain, watery non-bloody diarrhea . Pathogenesis: reduce absorption of water and sodium from GI

Rotavirus Norwalk virus

. Transmission by fecal-oral route . (+) ssRNA, nonenveloped virus . Persistent symptom about 1 week . Common in childhood . Treatment: conservative with fluid . Clinical , transmission, pathogenesis, replacement clinical course and treatment are similar to Rotavirus

9 Hepatitis virus

. Caused by respiratory tract infection and diarrhea . Classified 6 types - Hepatitis virus types A, B, C, D, E, G . Self limited disease . Intermittent epidermiology

Hepatitis A virus (HAV) virus (HBV)

. Naked RNA virus . Transmitted by :- blood transfusion, . Transmitted by fecal-oral route (food, water) intravenous drug use, sexual activity, . Common cause of hepatitis vertical transmission and contact body . Clinical:- fever, , nausea, vomiting secretion eg. semen, saliva, breast milk . Complete recovery . Clinical:- fever, jaundice, nausea, . No develop chronic hepatitis and vomiting . Diagnosis; HAV-IgM, IgG

10 (HBV)

. Cause of: - acute hepatitis with resolution - chronic hepatitis, and hepatocellular carcinoma - hepatitis with massive necrosis - result for hepatitis D virus infection - carrier

11 Interpretation serology of HBV

HBsAg Anti-HBs Anti-HBc Result

- - - ไมเคยติดเชื้อ ไมมีภูมิตานทาน ควรฉีดวัคซีนปองกัน

+ - - กําลังติดเชื้อ หรือเพิ่งเปนโรคนี้ ติดตอใหผูอื่นได

- - + เคยติดเชื้อมาไมนาน แตไมมีเชื้อแลว และไมติดตอไปยังผูอื่น Ground glass of HBV infection

Interpretation serology of HBV virus (HCV)

HBsAg Anti-HBs Anti-HBc Result . Transmitted by blood transfusion, + - + กําลังติดเชื้อ อาจเปนแบบ intravenous drug use, sexual activity, เฉียบพลัน หรือเปนพาหะเรื้อรัง and contact body secretion eg.

สามารถติดตอใหผูอื่นได semen, saliva . Asymptomatic of acute illness - + + เคยติดเชื้อมากอน และมีภูมิ ตานทานแลวจะไมติดเชื้อซ้ําอีก

- + - เคยฉีดวัคซีนปองกันโรค

12 (HCV) Hepatitis D virus (HDV)

. Cause of: . Transmitted by blood transfusion, - persistent infection and chronic hepatitis intravenous drug use, sexual activity, and contact body secretion - cirrhosis and hepatocellular carcinoma . Infected with HBV: - : expose to serum containing both HBV and HDV - superinfection: chronic carrier of HBV with new infection of HDV

Hepatitis D virus (HDV) virus (HEV)

. Clinical: . Transmitted by water-borne infection - acute hepatitis . High mortality rate in pregnant women - fulminant hepatitis . Self limited in most case - chronic hepatitis with cirrhosis . Complete recovery . No develop chronic hepatitis and hepatocellular carcinoma

13 Hepatitis Hepatitis B Hepatitis C Hepatitis D Hepatitis E Virus Virus Virus Virus Virus G Virus* Agent Icosahedra Enveloped Enveloped Enveloped Unenvelop ssRNA l capsid, dsDNA ssRNA ssRNA ed ssRNA virus ssRNA

Transmission Fecal- Parenteral; Parenteral; Parenteral; close Waterborne Parenteral oral close close contact contact contact

Incubation 2-6 wk 4-26 wk 2-26 wk 4-7 wk 2-8 wk Unknown Systemic with skin period None 0.1-1.0% of 0.2-1.0% of 1-10% in drug Unknown 1-2% of eruption blood blood addicts and blood donors in donors in hemophiliacs donors in Carrier state U.S. and U.S. and U.S. Western world Western world

Chronic None 5-10% of >50% <5% coinfection, None None hepatitis acute 80% upon superinfection Hepatocellular No Yes Yes No increase Unknown, None carcinoma above HBV but unlikely

Measles (nine-day/rubeola) Measles virus

. Measles virus . Virus multiplies in upper respiratory . Infected by respiratory droplet epithelium, lymphoid tissue, and spread . Common in children to blood . Immunity protect reinfection . Self limited disease . Incubation period 9-10 days . Vaccination is highly effective

14 Measles virus Measles virus

. Clinical: . Complication: - conjunctivitis, cough, coryza, fever - pneumonia - at day 2-3: “Koplik spot” at buccal - encephalitis mucosa - keratitis - at day 4-5: reddish-brown rash, - abnormal hemorrhage enlarged cervical LN - secondary bacterial infection - 1 week: subside

Measles Pathology of Measles

. Multinucleated giant cells with intranuclear and intracytoplasmic inclusion (Warthin- Finkeldey cells) in lymphoid organs and Koplik spot other organs Warthin-Finkeldey cells

15 Rubella (german measles) Rubella (german measles) . Caused by Rubella virus . Incubation period 14-21 days . Systemic infection : rash, fever, malaise, coryza, arthritis and arthralgias . Exanthem - discrete, pinkish red, fine maculopapular eruption - begins on the face and spreads cephalocaudally . Dx: serology testing

Congenital rubella syndrome Rubella (german measles)

. Infected pregnant woman ( first 20th wks) . Fetal death, premature delivery, congenital . Complications - arthritis, purpura, anomalies thrombocytopenia, encephalitis . Heart defects: PDA, VSD, pulmonary valvular stenosis . Eye and ear defects: cataract, glaucoma, deafness . CNS defects: microcephaly, mental retard

16 Herpes simplex infections Herpes simplex infection

HSV-1 Transmitted by direct/sexual contact >90% of primary infections are subclinical Diagnosis: clinically Fever blister or cold sores at facial HSV-1 Cold sore scrap base of vesicle and a special skin eg. lip, nose, gingivostomatitis stain - Giemsa-stained (Tzanck smear) ballooned epithelial cells with intranuclear HSV-2 inclusions and multinucleated giant genital pathogen viral cultures take 24-72 hours neonatal herpes

HSV-2 Genital Herpes

Primary herpes simplex infections Primary herpes simplex infections

Herpetic gingivostomatitis Skin infections high fever, irritability, , mouth pain, fever, malaise, localized lesions drooling in infants and toddlers direct inoculation (usually cold sores) and gingiva becomes intensely erythematous, genitalia edematous, friable and tends to bleed painful vesicles on erythematous base - small yellow ulcerations with red halos seen on usually grouped buccal and labial mucosa, tongue, gingivae, palate, tonsils

17 Recurrent herpes simplex infection Herpes simplex virus

. Gross: Triggers include fever, sunlight, local - group of intraepithelial vesicles trauma, menses, emotional stress (blisters) and frequently crust covering Seen most commonly as cold sores - may be ulcer Prodome of localized burning, itching . Pathology: before eruption of grouped vesicles - pink to purple, glassy intranuclear inclusion (Cowdry type A) - mononucleated or multinucleated cells

HSV (cold sores) HSV (gingivostomatitis)

18 HSV (genital herpes) HSV

glassy intranuclear inclusion (mononucleated or multinucleated cells)

Pathogenesis of HSV Pathogenesis of HSV

Initial infection in skin or mucous membrane travel along sensory nerve ending and retrograde axonal flow to neuron in dorsal root ganglia (latent infection) reactivate of latent infected neuron (eg. stress, fever, UV) newly replicated virus is transported anterograde to a site at or near portal of entry into body causing localized vesicles

19 Neonatal herpes infection Varicella zoster virus (VZV)

. Infected fetus by contact vaginal secretion . Cause of chickenpox, herpes zoster contains (shingles) . Clinical features . Incubation period ranges from 10-20 - mucocutaneous vesicles days - virus spread to other organs eg. brain, . Transmitted by inhalation of airborne liver, lung respiratory droplets from an infected host or direct contact . High mortality rate

Varicella zoster virus (VZV) Varicella (chickenpox)

. Primary acute infection of VZV: Clinical : fever, diffuse vesicle on skin and “chickenpox” . mucous membrane . Reactivation of latent VZV: “shingles or . Complications : secondary bacterial skin herpes zoster” distributes to sensory nerves infections, pneumonia, hepatitis, encephalitis, Reye syndrome . Severe in the immunocompromised host . Tx: Varicella-zoster immunogloblin

20 Herpes zoster (shingles) Pathogenesis of VZV

After primary infection, virus lies dormant Primary infection ( chickenpox) in genome of sensory nerve root cell VZV spread from mucosal and epidermal lesions Postulated triggers include mechanical to local sensory nerves and trauma, infection, immunosuppression Lesions are grouped, thin-walled vesicles VZV remains latent in dorsal ganglion cells of sensory nerves on erythematous base distributed along dermatome Reactivation of VZV results in syndrome of herpes zoster (shingles)

Varicella zoster virus (VZV) Varicella (chickenpox)

. Gross: - chickenpox: diffuse, scattered vesicles - shingles: vesicles distribution along the peripheral nerve (dermatome) . Histology: - Intranuclear inclusion of infected cells (multinucleated cells) lesions in multi-stages

21 Shingles Shingles

VZV Coxsackie Virus

. Type A . Causes herpangina and hand- foot-mouth disease . Type B . Causes Pluerodynia . Both . Causes meningitis, myocarditis and , also can cause juvenile diabetes Intranuclear inclusion

22 Hand-Foot-Mouth disease Hand-foot-and-mouth disease

Coxsackie Virus A, B or Enterovirus71 Common in child Prodome : low-grade fever, malaise, sore mouth, anorexia 1-2 days later : - oral lesions (tongue, throat, gum) : shallow, yellow ulcers surrounded by red halos - painful red blister on hand and foot Rx : supportive treatment

Herpangina

• Coxsackie Virus A Systemic with • Common in child hematopoietic • Infection of the throat • Causes red-ringed disorder blisters or ulcers on tonsils, roof of mouth and tongue

23 Cytomegalovirus (CMV) Cytomegalovirus (CMV)

. Produce a variety of disease depend . Transmitted by: on age, immune status - intrauterine transmission . Cause of asymptomatic in healthy - perinatal transmission person or severe systemic infection in - breast milk neonates and immunocompromised host (opportunistic infection) - respiratory droplets - semen and vaginal fluid - blood transfusion - organs transplantation

Cytomegalovirus (CMV) Histology of CMV

. Clinical feature depends on infected . Large purple intranuclear inclusion organs surrounded by clear halo and smaller . Congenital CMV infection basophilic intracytoplasmic inclusion . 90% asymptomatic . Organ involvement: salivary glands, . 10% symptomatic eg. hemolytic anemia, kidney, liver, pancreas, brain, ect. jaundice, thrombocytopenia, pneumonia, hepatosplenomegaly, retinitis, brain damage, mental retard or dead

24 CMV Epstein-Barr Virus (EBV)

. Cause of . Self-limiting illness of children & young . EBV associated with hairy leukoplakia, lymphoma, and . Transmitted by contact saliva

Epstein-Barr Virus (EBV) Pathogenesis

. Clinical of infectious mononucleosis: EBV replicates in B-lymphocytes in tonsil - fever - generalized lymphadenopathy B-lymphocytes disseminates in circulation - hepatosplenomegaly - sore throat (patch on tonsil) Atypical T lymphocytes in blood circulation - may be CNS lesion - may be hepatitis, pneumonia

25 Epstein-Barr Virus (EBV)

Diagnosis:

Lymphocytosis + atypical lymphocytes

Elevated liver enzymes

Heterophil antibodies - specific

Specific EBV antibody titers and PCR

Human Immunodeficiency Virus Atypical T lymphocytes (HIV)

. single-stranded, enveloped RNA viruses . HIV 1, HIV 2 . can lead to acquired immunodeficiency syndrome (AIDS)

26 Human Immunodeficiency Virus Human Immunodeficiency Virus (HIV) (HIV)

. Infection occurs by transfer of blood, . Primarily infects in helper T cells (CD4+ T cells), semen, vaginal fluid, or breast milk , and dendritic cells . 4 major routes of transmission . HIV infection leads to low levels of CD4+ T cells by 3 main mechanisms - sexual intercourse - direct viral killing of infected CD4+ T cells - contaminated needles - increased rates of apoptosis in infected CD4+ - breast milk T cells - killing of infected CD4 T cells by CD8 - vertical transmission + cytotoxic lymphocytes that recognize infected cells

Human Immunodeficiency Virus HIV structure (HIV)

. CD4+ T cell numbers decline below a critical level, cell-mediated immunity(CMI) is lost, and the body becomes progressively more susceptible to opportunistic infections

27 HIV infection 4 stages

. Incubation period - asymptomatic , 2-4 weeks after infection Replication cycle . Acute infection - rapid viral replication - fever, lymphadenopathy - pharyngitis (sore throat) - rash, myalgia, malaise - mouth and esophageal sores

HIV infection 4 stages HIV infection 4 stages

. AIDS . Latency stage - symptoms of various opportunistic infections - shows few or no symptoms - early : oral candidiasis (thrush) and tuberculosis - low level viral particle in blood stream - later : recurrences of HSV, shingles and pneumonia caused by Pneumocystis jirovecii - duration 2 weeks -20 years - final stages : CMV, Mycobacterium avium complex (MAC) and EBV induced B-cell lymphomas or Kaposi ‘s sacroma

28 Arbovirus and hemorrhagic fever

Dengue virus Dengue virus

. Dengue virus 1-4 . Infection with one serotype provides . Dengue fever is a vector-borne disease lifelong immunity to that particular . Transmitted via bite of mosquitoes serotype but not to the other three eg. Aedes aegypti, Aedes albopictus . Symptoms of dengue include: . Previous infection with simple dengue - high fever, headache fever greatly increases risk of developing - rash DHF - nausea and vomiting - myalgia - leukopenia (neutropenia), thrombocytopenia

29 Human papilloma virus (HPV)

. Most common causes of sexually Warty growths transmitted infection (STI) in the world . HPV types cause benign skin wart, anogenital warts, anogenital cancer

. Warts: proliferative squamous epithelium producing nodules or flat lesions

Human papilloma virus (HPV) Human papilloma virus (HPV)

. Skin warts . Anogenital warts (condyloma acuminatum) - HPV types 1,2 - HPV types 6,11 - common warts (verruca vulgaris): - warts at penis, vulva, vagina, anus hands, trunk, extremities - no associated with cancer - plantar warts: plantar . Anogenital cancer (squamous cell carcinoma) - no associated with cancer - HPV types 16,18,31,45 - cause of cancer of anus, vulva, cervix and penis

30 Human papilloma virus (HPV) Skin warts

. Transmitted by skin-to-skin contact during sexual intercourse . Treated by electrocautery, laser treatment . Histology : koilocytosis of infected cells

Anogenital warts Squamous cell carcinoma of cervix (condylomata acuminata)

31 Koilocytosis of infected cells Molluscum virus

. Cause of molluscum contagiosum . Self-limited viral disease of skin . Transmitted by skin or sexual contact . Gross: raised, umbilicated, cutaneous nodules at skin (most perineum) . Histology: intracytoplasmic inclusion bodies (molluscum bodies)

Pathogenesis Molluscum contagiosum

transmitted primarily through direct skin contact with an infected individual virus infects epidermis causing hyperplasia, hypertrophy and central degeneration of the epidermis

epidermis has molluscum bodies contain large numbers of maturing virions

32 intracytoplasmic inclusion bodies Intracytoplasmic inclusion bodies (molluscum bodies) (molluscum bodies)

Poliovirus

. Causes poliomyelitis Central nervous . Transmitted by fecal-oral route system . Most asymptomatic . 1/100 of infected patientsdisease (spinal poliomyelitis, bulbar poliomyelitis)

33 Pathogenesis Poliomyelitis Poliovirus infects oropharynx secreted in saliva and swallow . Clinical features Multiplies in intestinal mucosa and lymph nodes - flaccid paralysis - muscle atrophy Hematogenous spreading - hyporeflexia Invade to CNS and repilcate in spinal cord (spinal poliomyelitis), or brain stem (bulbar poliomyelitis)

* Virus destroys motor neuron in anterior horn of spinal cord or brain stem*

Rabies virus

. Cause of rabies (encephalitis) . Post-exposure prophylaxis: combined . Transmitted by saliva of dog or cat bites immune serum and vaccine . Clinical: . High mortality rate - malaise, headache, fever, dysphagia fallowed by period of acute neurologic symptom including disorientation, hallucination, seizure, and dead from res. failure

34 Pathogenesis Negri bodies

Rabies virus multiplies at site of local bite travel to CNS through the peripheral nerves

replicates in neurons of CNS

Clinical symptom

Intracytoplasmic inclusion in neuron

Arbo virus

. Japanese B caused by encephalitis . Animal host : pig . Carrier : Culex mosquitoes THE END . Clinical : confusion, seizure, coma . Pathology : mononuclear cells around vessels, necrosis of neuron and brain tissue

35