Hepatitis C virus.

 It is most often mild and anicteric but occasionally severe with fulminant hepatic failure. It is caused an RNA virus, which may be transmitted parenterally (a cause of post-transfusion hepatitis); the route of transmission undetermined in 40%-50% of cases
a. 90% of blood transfusion-related hepatitis is caused by hepatitis C.
b. 50% progress to chronic disease.
c. Increased risk for hepatocellular carcinoma.

d. Incubation period: ranges from 2 to 26 weeks, but averages 8 weeks.
-  Antibody is detected by enzyme-linked immunosorbent,assay (ELISA). The incubation period is between 2 and weeks with peak onset of illness 6-8 weeks after infection 
- Most patients progress to chronic liver disease, specifically chronic persistent hepatitis or chronic active hepatitis 
- Cirrhosis is common in patients with chronic active hepatitis and occurs in 20%-25% of infected patients. HCV is also associated with hepatocellular carcinoma.

e. Treatment and prevention: α-interferon is used to treat chronic hepatitis C. There is currently no vaccine available.

Hepatitis B virus (“serum hepatitis”)
- Hepatitis B (HBV) may cause acute hepatitis, a carrier state, chronic active disease, chronic persistent disease, fulminant hepatitis, or hepatocellular carcinoma  
- It is caused by a DNA virus, the virions are called Dane particles. 

b. Incubation period: ranges from 4 to 26 weeks, but averages 6 to 8 weeks.
a. Symptoms last 2 to 4 weeks, but may be asymptomatic.
c. The hepatitis B viral structure has also been named the Dane particle.

Transmission is through contact with infected blood or other body fluids. It can be transmitted by sexual intercourse and is frequently transmitted to newborns of infected mothers by exposure to maternal blood during the birth process
- Associated antigens include core antigen (HBcAg) and surface antigen (HBsAg).
The latter is usually identified in the blood for diagnosis. HbsAg is the earliest marker of acute infection.
HBeAg is also associated with the core. Its presence indicates active acute infection; when anti-HBeAg appears, the patient is no longer infective
- HBV is associated with hepatocellular carcinoma; HBsAg patients have a 200-fold greater risk of hepatocellular carcinoma than subjects who have not been exposed. 

Antibodies  
- Antibodies to surface antigen (anti-HBs) are considered protective and usually appear after the disappearance of the virus.
-Antibodies to HBcAg are not protective. They are , detected just after the appearance of HBsAg and are used to confirm infection when both HBsAg and anti HBs are absent (window).
- Antibodies to HBeAg are associated with a low risk of infectivity.

d. Infection increases the risk for hepatocellular carcinoma.

e. Laboratory assay of hepatitis B antigens and antibodies:

(1) HBsAg—present only in acute infection or chronic carriers.
(2) HBsAb—detectable only after 6 months post-initial infection. HBsAb is present in chronic infections or vaccinated individuals. Note: HBsAb is also being produced during acute infections and in chronic carriers; however, it is not detectable via current laboratory methods.
(3) HBcAg—present in either acute or chronic infection.
(4) HBeAg—present when there is active viral replication. It signifies that the carrier is highly infectious.
(5) HBeAb—appears after HBeAg. It signifies that the individual is not as contagious.

f. Vaccine: contains HBsAg.

g. Prevention: immunoglobulins (HBsAb) are available.

Nonspecific or Innate Immunity

1. Genetic factors

• Species: Guinea pig is very susceptible to tuberculosis.
• Race: Negroes are more susceptible to tuberculosis than whites
• Sickle cells (HbS-a genetic determined Haemoglobinopathy resistant to Malarial parasite.

2. Age Extremes of age are more susceptible.

3. Hormonal status. Low resistance in:

• Diabetes Mellitus.
• Increased corticosteroid levels.
• Hypothyroidism

4. Phagocytosis. Infections can Occur in :

• Qualitative  or quantitative defects in neutrophils and monocytes.
• Diseases of mononuclear phagocytic system (Reticuloendothelial cells-RES).
• Overload blockade of RES.

5. Humoral factors

• Lysozyme.
• Opsonins.
• Complement
• Interferon (antiviral agent secreted by cells infected by virus)

Hepatitis D virus—can only infect cells previously infected with hepatitis B. 
 Delta hepatitis (HDV) is associated with a 35-nm RNA virus composed of a delta antigen-bearing core surrounded by HBV's Ag coat;

HDV requires HBV for replication.

Delta hepatitis can cause quiescent HBV states to suddenly worsened . Its transmission is the same as that of HBV.
 
 Hepatitis E virus—a high mortality rate in infected pregnant women.

Hepatitis E (HEV) is caused by a single-stranded RNA virus. The disease is typically self-limited and does not evolve into chronic hepatitis; it may, however, be cholestatic.

Pregnant women may develop fulminant disease.

Transmission is by the fecal oral route.

HEV occurs mainly in India, Nepal, Pakistan, and Southeast Asia.
 

Chemical Mediators In Inflammation

Can be classified as :

A. Neurogenic

Also called the Triple Response of Lewis. It involves neurogenic vasodilatation of arterioles due to antidromic axon reflex arc. The constituents of the response are:

1. arteriolar vasoconstriction followed by

2. arteriolar vasodilatation

3. swelling

B. Chemical

1. Amines: Histamine and 5 hydroxytryptamine. Released  from platelets and mast cells.

Actions: Immediate and short lived.

Dilatation of arterioles.

Increased capillary premeability.

Kinins: Bradykinin and kallidin These are present in inactive from and are  activated by kinin forming proteases

Actions:

Arteriolar dilatation.

Increased vascular permeability

Pain

Kinin forming proteases Plasmin and Kallikrein. Present as inactive precursors.

Cleavage products of complement C₃a und C₅a are called anaphylatoxins

Actions:

Histamine release from mast cells

Chemotaxis (also C₅₆₇ )

Enhance phagocytosis.

 Polymorph components

Cationic: proteins which cause

Increased permeability

Histamine release.

Chemotaxis of monocytes

Neutral proteases which:

Cleave C3 and C5 to active form

Convert Kininogen to Kinin

Increase permeability.

Acid proteases which liberate leucokinins

Slow reacting. substance of anaphylaxis: (SRS-A) is a lipid released from mast cell.

Action --Increases vascular permeability

Prostaglandins: E1 + E2 _.

Platelets are rich source

Action:

Platelets are a rich source.

Vasodilatation.

Increased permeability.

Pain.

VIII. Miscellaneous: like

Tissue lactic acid.

 Bacterial toxins.

Tuberculosis

Causative organism

-Mycobacterium tuberculosis 
-Strict aerobe 
-Pathogenic strains
-hominis, bovis, avium, murine& cold blooded vertebrate strain 

Koch’s bacillus
-small slender, rod like bacillus, 4umnon-motile, aerobic -high lipid content 
-divides every 16 to 20 hours, an extremely slow rate 
-stains very weakly Gram-positive or does not retain dye due to the high lipid & mycolicacid content of its cell wall 
-can withstand weak disinfectant and survive in a dry state for weeks. 

Demonstrated by 
-ZiehlNeelsenstaining 
-Fluorescent dye method 
-Culture in LJ media 
-Guinea pig inoculation

Modes of transmission

Inhalation , Ingestion, Inoculation , Transplacental

Route Spread 
Local , Lymphatic , Haematogenous , By natural passages, 

Pathogenesis 

- Anti‐mycobacterial CMI, confers resistance to bacteria → dev. of HS to tubercular Ag 
- Bacilli enters macrophages 
- Replicates in phagosomeby blocking fusion of phagosome&  lysosome, continues for 3 weeks →bacteremiabut  asymptomatic 
- After 3 wks, T helper response is mounted by  IL‐12 produced  by macrophages 
- T cells produce IFN, activates macrophages → bactericidal  activity, structural changes 
- Macrophages secrete TNF→ macrophage recruitment,  granuloma& necrosis

Fate of granuloma 
- Caseousmaterial undergo liquefaction---cold abscess 
- Bones, joints, lymph nodes & epididymis---sinuses are formed & sinus tract lined by tuberculousgranulation tissue 
- Dystrophic calcification

Types of TB

1. Primary Pulmonary TB 
2. secondary TB (miliary, fibrocaseous, cavitary) 
3. Extra-pulmonary TB (bone, joints, renal, adrenal, skin… )

Primary TB
Infection in an individual who has not been previously infected or immunised 
Primary complex 
Sites
    -lungs, hilarlymph nodes 
    -tonsils, cervical lymph nodes 
    -small intestine, mesenteric lymph nodes

Primary TB
In the lung, Ghon’scomplex has 3 components: 
1. Pulmonary component -Inhalation of airborne droplet ~ 3 microns. 
    -Bacilli locate in the subpleuralmid zone of lung 
    -Brief acute inflammation –neutrophils. 
    -5-6 days-invoke granulomaformation. 
    -2 to 8 weeks –healing –single round ;1-1.5 cm-Ghon focus. 
2. Lymphatic vessel component 
3. Lymph node component

Fate of primary tuberculosis

- Lesions heal by fibrosis, may undergo calcification, ossification 
    -a few viable bacilli may remain in these areas  
    -bacteria goes into a dormant state, as long as the person's immune system remains active 
- Progressive primary tuberculosis: primary focus continues to grow & caseousmaterial disseminated to other parts of lung 
- Primary miliarytuberculosis: bacilli may enter circulation through erosion of blood vessel 
- Progressive secondary tuberculosis: healed lesions are reactivated, in children & in lower resistance

Secondary tuberculosis

-Post-primary/ reinfection/ chronic TB 
-Occurs in immunized individuals. 
-Infection acquired from 

    -endogenous source/ reactivation 
    -exogenous source/ reinfection 

Reactivation
-when immune system is depressed 
-Common in low prevalence areas. 
-Occurs in 10-15% of patients 
-Slowly progressive (several months) 

Re-infection 
-when large innoculum of bacteria occurs 
-In areas with increased personal contact

Secondary TB

-Sites-Lungs 1-2 cm apical consolidation with caseation 
-Other sites -tonsils, pharynx, larynx, small intestine & skin

Fate of secondary tuberculosis

•Heal with fibrous scarring & calcification 
•Progressive secondary pulmonary tuberculosis: 
    -fibrocaseoustuberculosis 
    -tuberculouscaseouspneumonia 
    -miliarytuberculosis

Complications: 
a) aneurysm of arteries–hemoptysis 
b) bronchopleuralfistula 
c) tuberculousempyema 

MiliaryTB

• Millet like, yellowish, firm areas without caseation 
• Extensive spread through lympho-hematogenousroute 
• Low immunity 
• Pulmonary involvement via pulmonary artery 
• Systemic through pulmonary vein: 
    -LN: scrofula, most common 
    -kidney, spleen, adrenal, brain, bone marrow

Signs and Symptoms of Active TB

• Pulmonary-cough, hemoptysis, dyspnea 
• Systemic: 
• fever 
• night sweats 
• loss of appetite 
• weight loss 
• chest pain,fatigue 

•If symptoms persist for at least 2 weeks, evaluate for possible TB infection

Diagnosis

•Sputum-Ziehl Neelsen stain –10,000 bacilli, 60% sensitivity 
    -release of acid-fast bacilli from cavities intermittent. 
    -3 negative smears : low infectivity 

•Culture most sensitive and specific test.
     -Conventional Lowenstein Jensen media-10 wks. 
     -Liquid culture: 2 weeks 

•Automated techniques within days 
    should only be performed by experienced laboratories (10 bacilli) 

•PPD for clinical activity / exposure sometime in life 
•X-ray chest 
•FNAC

PPD Tuberculin Testing

- Read after 72 hours. 
- Indurationsize -5-10 mm 
- Does not d/s b/w active and latent infection 
- False +: atypical mycobacterium 
- False -: malnutrition, HD, viral, overwhelming infection, immunosuppression 
- BCG gives + result.

Tuberculosis Atypical mycobacteria 

- Photochromogens---M.kansasii 
- Scotochromogens---M.scrofulaceum 
- Non-chromogens---M.avium-intracellulare 
- Rapid growers---M.fortuitum, M.chelonei

5 patterns of disease 

- Pulmonary—M.kansasii, M.avium-intracellulare 
- Lymphadenitis----M.avium-intracellulare, M.scrofulaceum 
- Ulcerated skin lesions----M.ulcerans, M.marinum 
- Abscess----M.fortuitum, M.chelonei 
- Bacteraemias----M.avium-intracellulare as in AIDS