Lecture 39 to 42 Organ tissue infection

Question 1

Viral infections of the liver

Answer 1

• Hep A to G and TT virus
• Yellow fever virus
• Herpes viruses 1, 3, 4, 5
• Rubella (congenital rubella syndrome)

Question 2

Hep A

Answer 2

• naked, icosahedral picornaviridae family
• • ss RNA
• resists heating, disinfectants, heating, salt water, stomach pH
• sensitive to chlorine, formalin, and UV
• Etiopath:
  
  • fecal-oral route
  • incubation period: 15 to 45 d (short incubation period, infectious)
  • Entry: shellfish, oral and anal sex
  • virus shedding before sx
  • 2 weeks viremia
  • virus replicates in Kupffer’s cells and hepatocytes
• Sx: abrupt, sx, fever, nausea, vomiting and jaundice
  
  • recovery complete in 8 to 12 weeks
• non-lytic pircornavirus replicating without much pathology
• damage due to immunpath including CMI, immune complex, and complement
• does not initiate a chronic infectior or liver cancers
• daycare and restaurants
• Dx: ELISA
• Rx: passive Ig
• Control: handwashing, vaccination, inactivated vaccine

Question 3

Hep B

Answer 3

• Hepadnaviridae family
• partially ds DNA virus w sphrical, complex envelope w RT
• infected serum has dane particles and viral surface Ag (detectable)
• Etiopath: blood, sex, IV drugs, every bodily fluid is infectious
• strict liver tropism
• genome can integrate into host chromosome
• infected cells release HBsAg particles lacking DNA (just empty shells)
• Incubation period: 50 to 180 d

Question 4

surface antigen (HBsAg)

Answer 4

• S, M, L glycoproteins w common C-terminal;
• L-glycoprotein is the attachment protein and alos binds the envelope to the core
• pleomorphic

Question 5

soluble antigen (HbeAg)

Answer 5

• associated w core protein, cleavage product of viral core protein; does not assemble into virus; secrete into serum instead
• high HBV titers in serum
• indicator of serum infectivity

Question 6

core antigen (HBcAg)

Answer 6

• observed in infected hepatocytes
• has protein kinase activity
• no free HBcAg in serum bc HBcAg -> highly immunogenic -> tyr-arg content high

Question 7

Events during Hep B Acute infection

Answer 7

• HBeAg present in serum 1 to 3 mo
• HBsAg prsent in serum 1 to 5 mo
• anti-HBc-Ab 1st to appear
• No HBsAg and HBeAg during window period (5 mo); only anti-HBc Ab in window (Exam q)
• Note: Presence of HbSAg >6 mo = chronic state

Question 8

Development of chronic HBV carrier state

Answer 8

• NO WINDOW PERIOD
• viremia continues for years
• HBsAg and HBeAg detectable for years
• anti-HBc-Ab always present

Question 9

Control of HBV infections

Answer 9

• screening of all blood for HBsAg
• inactivated vaccines (Hepatavax) and recombinant vaccines (Recombivax) for high risk individuals

Question 10

Hep C

Answer 10

• icosahedral, enveloped flavivirus (+ ss RNA)
• HCV only flavivirus not transmitted thru insects
• reservoir: humans & chimps
• 70% persistent infection
• Transmission: sex (20%). IV drugs (60%), blood transfusions
• Incubation 40 to 120 d
• Predictor of disease is high ALT
• Epidemiology: Types 1b and 2 a/c commonly involved in HCC

Etiopath:

• virus coats itself w LDL & VLDL and enters hepatocytes via cell surface receptor
• bud from ER and remains there
• inhibits apoptosis and IFN-alpha by binding to TNF and protein kinase receptors to establish persistence (no cell death)
• proliferation: Beta-catenin/Wnt pathway -> MYC, cyclin D, WISP-2 in nucleus -> cell proliferation
• also core protein -> p21WAF1 (cyclin-dependent) -> inactivates p53
• other than hepatocytes, CD81 and other lymphocytes susceptible

Signs of chronic liver disease

• portal HPT
• jaundice
• scratch marks/pruritis due to obstructive jaundice
• finger clubbing
• palmar erythema
• shifting dullness on percussion of ab due to ascites
• tachycardia to anemia

Control:

• no vaccine bc multiple genotypes
• Pegylated IFN-alpha: Types 2 & 3 more responsive to IFN-alpha therapy than type 1b
• protease inhibitors: Bocepravir & Telaprevir

Rx: curable w combined oral therapy (unlike Hep B)

• Declastavir inhibits NS5A, RNA synthesis, viral assembly/secretion
• Sofosbuvir -> uridine analogue -> binds to NS5B (HCV DNAP)
• Labs: not cirrhotic
• PLT low due to unknown mechanism; splenomegaly

​

Question 11

Outcomes of HCV infection

Answer 11

• IL28B polymorphism alters outcome -> inactive or altered gene -> little/no virus clearance in non-icteric state (see fig.)
• virus persistence
  
  • mitochondria damage -> recruitment of Drp1 -> asymmetric fragmentation -> 1 healthy + 1 damaged mitochondria
  • Drp1 -> less interferon production
  • Drp1 -> inhibits apoptosis

Question 12

Hep D

Answer 12

• -ve ssRNA, circular, enveloped
• 4 genotypes by HLA epitope analysis
• requires presence of replicating HBV which provides the viral coat (containing HBsAg in addition to delta Ag)
• LARGE form HDAg: involved in viral packaging & suppressing HBV replication.
• small form HDAg: transactivating replication of HDV RNA.
• Transmission: blood and IV drugs
  
  • vertical transmission rare but possible
  • co-infection w HBV leads to severe and fatal course
  • HDV infection subsequent (super infection) to HBV results in milder hepatitis.
• Etiopath: still unclear
  
  • persistent infection assoc. w hepatic inflammation, incr. ALT, and interference of JAK-STAT pathway.
• Dx: anti-delta IgM and/or IgG
• Control: vaccinate high risk against Hep B
• Rx: higher IFN-alpha

Question 13

Hep E

Answer 13

• small, naked icosahedral + ss RNA virus
• Hepeviridae family
• Epi: 5 types
  
  • Types 1 & 2: humans (younger Pt)
  • 3 & 4: humans, pigs (older Pt)
  • 5: birds
• Transmission: fecal-oral, tranfusion, zoonotic
• Epi: contaminated water, S. and E. Asia
• Control: better hygience, no vaccines

Question 14

Hep G

Answer 14

• enveloped + ss RNA virus
• flaviviridae family
• transmisible to chimps
• Etiopath:
  
  • causes synctial giant cell hepatitis
• Control:
  
  • no vaccines, source of infection not known

Question 15

Hep TT

Answer 15

• icosahedral, naked -ss RNA, circular
• circinoviridae family
• Torque-Tine
  
  • index Pt
  • transfusion and dialysis transmitted hepatitis
• Epi: 12% of Japanese and 60-70% of Norwegians have anti-viral Ab
• At least 2 genotypes w many subtypes reported
• Transmission: dialysis, breastfeeding, sex, transplacental
• Control: no vaccines available

Question 16

Yellow Fever virus

Answer 16

• flavivirus, class IVa
• Vector: Aedes (Africa) & Hemagogus spp. (S. America)
• Incubation period: 6-7 d w abrupt fever, myalgia, prostration
• Sx: usually resolves in 4 to 5 d
  
  • severe cases include jaundice, hemorrhage, hemoptysis, collapse
• Dx: serology & PCR
• Prevention: live attenuated 17D strain; protection for 10 years
• Control: mosquito control

Question 17

Herpesviridae family summary

Answer 17

Alpha

• replication time: 6 to 8 h
• CPE: cytolytic
• Latency: neurons
• HHV-1, 2, 3

Beta

• replication time: 12 to 24 h
• CPE: cytomegaly
• Latency: glands
• HHV-5, 6, 7

Gamma

• replication cycle: variable
• HHV-4, 8
• CPE: lymphoproliferative
• latency: lymphoid

Question 18

HHV-4 (EBV)

Answer 18

• Epi: 15% of cases have hepatitis
  
  • 90% of population seropositive
• Etiopath: EBV binds to CD21 and goes latent in B cells
• Sx: atypical lymphocytosis, fever, liver failure is rare
  
  • asx in children bc immune system not fully developed
  • mononucleosis: pharyngitis, major fatigue, fever, lymphadenopathy, splenomegaly
    
    • C&C: no contact sports due to risk of splenic rupture
  • lymphoproliferative disease, hairy cell leukoplakia
  • malignancies: Burkitt’s lymphoma, nasopharyngeal carcinoma, Hodgkin lymphoma
• Dx: heterophile Ab, elevated transaminases & ALP & Downey cells on BS
• Prevention and control: no vaccine available

Question 19

HHV-5

Answer 19

• Epi: in developed countries, most people have Ab against CMV
• Sx: mostly subclinical
• Transmission: urine, breast milk, serum, semen, genital secretions; children shed virus for a long time
• Sx: usually asx in immunocompetent individuals
  
  • CMV retinitis
  • Heterophile -ve mononucleosis
  • blueberry muffin baby: transplacental transmission leading to thrombocytic purpura
• Dx: owl eye cells, cotton wool retinitis, RIA & ELISA, viral detection from urine and saliva, EM observation of virus in urine
• Rx:
  
  • Gancyclovir (CMV resistant to Acyclovir bc it lacks viral thymidine kinase);
  • human leukocyte IFN

Question 20

Leptospirosis

Answer 20

• transmission: zoonotic and from contaminated water; most common from leptospira interogans
• incubation period: 1 to 3 wk
• Sx: severe Weil disease (jaundice & renal failure), meningitis, nephritis, rash, hemmorrhage (in severe cases), early myalgia, hepatitis, renal disease, conjunctivitis, thrombocytopenia

Question 21

Granulomatous hepatitis

Answer 21

• non-infectious causes include vasculitis and quinine
• infectious causes include
  
  • Coxiella burnetti
  • Mycobacteria
  • Histoplasma capsulatum
  • Brucella

Question 22

Liver abscesses

Answer 22

• liver abscess can be a common cause of pyrexia of unknown origin
• jaundice rare
• elevated ALP and ESR
• Bacterial causes
  
  • E. Coli
  • Klebsiella
  • Serratia
  • other enterobacteriae
  • enterococcus
  • Staph. milleri
  • Staph. Aureus
• Amoebic
  
  • Entomoeba histolytica
• Schistosome
  
  • S. mansoni
  • S. japonicum
  • S. haematobium
• Hydatids
  
  • Echinococcus granulosus
  • Echinococcus multilocularis
• Fasciola hepatica and other flukes

Question 23

hepatitis in the neonate or immunocompromised

Answer 23

• HHV-1, 3, 5
• rubella

Question 24

Viral Infections of eyes

Answer 24

• adenoviruses most common cause of eye infections
• Epi: in healthy individuals, adenovirus can be found in tonsils, nasopharynx, and intestinal tract.
• Transmission: oro-fecal and respiratory tract
• sx: respiratory, renal, gastro
  
  • respiratory: fever, rhinitis, cough, exudative pharyngitis (< 3 YO)
  • acute & chronic conjunctivitis, laryngitis, croup, pharyngoconjunctivitis, bronchitis, pneumonia
  • hemorrhagic cystitis: hematuria
  • gastroenteritis
• Etiopath:
  
  • direct innoculation to nasal or conjuctival mucosa by hands or towel
  • adenovirus enters and replicates in epthelial cells producing cell necrosis and inflammation
  • viremia spreads to lymphoid tissue, kidney, bladder
• Pathology
  
  • epithelial cell necrosis w mononuclear cell inflammation.
  • intranuclear inclusions (Cowdry type A) seen in some cases
  • Dx: virus isolation, 4x increase in Ab titers
  • Prevention and control: inactivated vaccine (serotype 3, 4, 7); live vaccine reccomended for military

Question 25

Bacterial Infections of Eyes

Answer 25

* Chlamydia trachomatis * Epi: spread thru contact; serotypes A-C -\> trachoma (granular conjunctivitis) and blindess; serotypes D-K -\> conjunctivits; some serotypes can infect urinary tract and cause conjuctivitis in neonates * N. menigitidis: most common; conjunctiva neonaturm * N. catarrahalis: cataracts in areas w sand and limited water * S. Aureus: purulent infections of the eyes

Question 26

Fungal endophthalmitis

Answer 26

* fusarium incarnatum * bipolaris hawaiiensis

Question 27

Infection of parotids and testes

Answer 27

* mumps virus * paramyxovirus: enveloped virus w helical nucleocapsid containing - ss RNA * 3 major peplomers (HA, NA, F) * neutralizing Ab persists for years * Transmission: droplets and saliva contract * Incubation: 2- 3 wk * Epi: affects children 5 to 9 yo during winter and spring every 3 wks; immunity from natural infection is lifelong * Sx: * parotitis most common * meningitis * orchitis common in adult males * additional complications include Cochlear inflammation, Arthritis, Mastitis, Myocarditis * Note: Pt infectious before any sx; virus shed through urine and saliva * Dx: RT-PCR, ELISA, HI, neutralizing Ab * Prevention and control: MMR vaccination