VIRAL DISEASES

RABIES (Hydrophobia)

An acute infectious disease of mammals, especially carnivores, characterized by CNS pathology leading to paralysis and death.

Etiology and Epidemiology

Rabies is caused by a neurotropic virus often present in the saliva of rabid animals

Pathology

The virus travels from the site of entry via peripheral nerves to the spinal cord and the brain, where it multiplies; it continues through efferent nerves to the salivary glands and into the saliva.

microscopic examination shows perivascular collections of lymphocytes but little destruction of nerve cells. Intracytoplasmic inclusion bodies (Negri bodies), usually in the cornu Ammonis, are pathognomonic of rabies, but these bodies are not always found.

Sign/Symptoms

In humans, the incubation period varies from 10 days to > 1 yr and averages 30 to 50 days.

Rabies commonly begins with a short period of depression, restlessness, malaise, and fever. Restlessness increases to uncontrollable excitement, with excessive salivation and excruciatingly painful spasms of the laryngeal and pharyngeal muscles. The spasms, which result from reflex irritability of the deglutition and respiration centers, are easily precipitated Hysteria due to fright

Prognosis and Treatment

Death from asphyxia, exhaustion, or general paralysis usually occurs within 3 to 10 days after onset of symptoms

THE THYROID GLAND

The thyroid gland develops embryologically from the developing pharyngeal epithelium that descends from the foramen cecum at the base of the tongue to its normal position in the anterior neck. This pattern of descent explains the occasional presence of ectopic thyroid tissue, most commonly located at the base of the tongue (lingual thyroid) or at other sites abnormally high in the neck. 

Eosinopenia:
Causes

-Corticoid effect (Cushing's syndrome or therapy).
-Stress.

Haemolysis due to drugs and chemicals

This can be caused by :

1. Direct toxic action.
    -> Naphthalene.
    -> Nitrobenzene.
    -> Phenacetin.
    -> Lead.

Heinz bodies are seen in abundance.

2. Drug action on G-6-PD deficient RBC
3. Immunological mechanism which may be : 
    -> Drug induced  autoantibody haemolysis, Antibodies are directed against RBC.
    -> Hapten-cell mechanism where antibodies are directed against which is bound to cell surface e.g. Penicilin.
 

Gout
This is a disorder caused by the tissue accumulation of excessive amounts of uric acid, an end product of purine metabolism. It is marked by recurrent episodes of acute arthritis, sometimes accompanied by the formation of large crystalline aggregates called tophi & chronic joint deformity. All of these are the result of precipitation of monosodium urate crystals from supersaturated body fluids. Not all individuals with hyperuricemia develop gout; this indicates that influences besides hyperuricemia contribute to the pathogenesis. Gout is divided into primary (90%) and secondary forms (10%). 

Primary gout designates cases in whom the basic cause is unknown or when it is due to an inborn metabolic defect that causes hyperuricemia.

In secondary gout the cause of the hyperuricemia is known.

Pathologic features 

The major morphologic manifestations of gout are
1. Acute arthritis
2. Chronic tophaceous arthritis
3. Tophi in various sites, and
4. Gouty nephropathy

Acute arthritis

- The synovium is edematous and congested,
- There is an intense infiltration of the synovium & synovial fluid by neutrophils.
- Long, slender, needle-shaped monosodium urate crystals are frequently found in the cytoplasm of the neutrophils as well as in small clusters in the synovium.

Chronic tophaceous arthritis:

- This evolves from repetitive precipitation of urate crystals during acute attacks. The urates can heavily encrust the articular surfaces and form visible deposits in the synovium.
- The synovium becomes hyperplastic, fibrotic, and thickened by inflammatory cells, forming a pannus that destroys the underlying cartilage, and leading to erosions of subjacent bone.
- In severe cases, fibrous or bony ankylosis occurs, resulting in loss of joint function. 

Tophi

These are the pathognomonic hallmarks of gout.
- Tophi can appear in the articular cartilage, periarticular ligaments, tendons, and soft tissues, including the ear lobes. Superficial tophi can lead to large ulcerations of the overlying skin.
- Microscopically, they are formed by large aggregations of urate crystals surrounded by an intense inflammatory reaction of lymphocytes, macrophages, and foreign-body giant cells, attempting to engulf the masses of crystals.

Gouty nephropathy

- This refers to the renal complications associated with urate deposition including medullary tophi, intratubular precipitations and renal calculi. Secondary complications such as pyelonephritis can occur, especially when there is urinary obstruction.

Pathogenesis

- Although the cause of excessive uric acid biosynthesis in primary gout is unknown in most cases, rare patients have identifiable enzymatic defects or deficiencies that are associated with excess production of uric acid.
- In secondary gout, hyperuricemia can be caused by increased urate production (e.g., rapid cell lysis during chemotherapy for lymphoma or leukemia) or decreased excretion (chronic renal failure), or both. Reduced renal excretion may also be caused by drugs such as thiazide diuretics, because of their effects on uric acid tubular transport.
- Whatever the cause, increased levels of uric acid in the blood and other body fluids (e.g., synovium) lead to the precipitation of monosodium urate crystals. The precipitated crystals are chemotactic to neutrophils & macrophages through activation of complement components C3a and C5a fragments. This leads to a local accumulation of neutrophils and macrophages in the joints and synovial membranes to phagocytize the crystals. The activated neutrophils liberate destructive lysosomal enzymes. Macrophages participate in joint injury by secreting a variety of proinflammatory mediators such as IL-1, IL-6, and TNF. While intensifying the inflammatory response, these cytokines can also directly activate synovial cells and cartilage cells to release proteases (e.g., collagenases) that cause tissue injury.

- Repeated bouts of acute arthritis, however, can lead to the permanent damage seen in chronic tophaceous arthritis.

b Pseudogout (chondrocalcinosis) (Calcium pyrophosphate crystal deposition disease). Pseudogout typically first occurs in the age 50 years or older. It involves enzymes that lead to accumulation and eventual crystallization of pyrophosphate with calcium. The pathology in pseudogout involves the recruitment and activation of inflammatory cells, and is reminiscent of gout. The knees, followed by the wrists, elbows,
shoulders, and ankles, are most commonly affected. Approximately 50% of patients experience significant joint damage.

Infectious Arthritis can cause rapid joint destruction and permanent deformities. Microorganisms can lodge in joints during hematogenous dissemination, by direct inoculation or by contiguous spread from osteomyelitis or a soft tissue abscess.

Suppurative Arthritis is a subtype of infectious arthritis in which the bacteria seed the joint during episodes of bacteremia. Haemophilus influenzae predominates in children under age 2 years, S. aureus is the main causative agent in older children and adults, and gonococcus is prevalent during late adolescence and young adulthood. 

There is sudden onset of pain, redness, and swelling of the joint with fever, leukocytosis, and elevated ESR. In 90% of nongonococcal suppurative arthritis, the infection involves only a single joint-usually the knee. Joint aspiration is typically purulent, and allows identification of the causal agent. 

Osteomyelitis
This refers to inflammation of the bone and related marrow cavity almost always due to infection. Osteomyelitis can be acute or a chronic. The most common etiologic agents are pyogenic bacteria and Mycobacterium tuberculosis.

Pyogenic Osteomyelitis

The offending organisms reach the bone by one of three routes:
1. Hematogenous dissemination (most common)
2. Extension from a nearby infection (in adjacent joint or soft tissue)
3. Traumatic implantation of bacteria (as after compound fractures or orthopedic procedures). Staphylococcus aureus is the most frequent cause. Mixed bacterial infections, including anaerobes, are responsible for osteomyelitis complicating bone trauma. In as many as 50% of cases, no organisms can be isolated. 

Pathologic features 

• The offending bacteria proliferate & induce an acute inflammatory reaction.
• Entrapped bone undergoes early necrosis; the dead bone is called sequestrum.
• The inflammation with its bacteria can permeate the Haversian systems to reach the periosteum. In children, the periosteum is loosely attached to the cortex; therefore, sizable subperiosteal abscesses can form and extend for long distances along the bone surface.
• Lifting of the periosteum further impairs the blood supply to the affected region, and both suppurative and ischemic injury can cause segmental bone necrosis.
• Rupture of the periosteum can lead to an abscess in the surrounding soft tissue and eventually the formation of cutaneous draining sinus. Sometimes the sequestrum crumbles and passes through the sinus tract.
• In infants (uncommonly in adults), epiphyseal infection can spread into the adjoining joint to produce suppurative arthritis, sometimes with extensive destruction of the articular cartilage and permanent disability.
• After the first week of infection chronic inflammatory cells become more numerous. Leukocyte cytokine release stimulates osteoclastic bone resorption, fibrous tissue ingrowth, and bone formation in the periphery, this occurs as a shell of living tissue (involucrum) around a segment of dead bone. Viable organisms can persist in the sequestrum for years after the original infection.
Chronicity may develop when there is delay in diagnosis, extensive bone necrosis, and improper management. 

Complications of chronic osteomyelitis include
1. A source of acute exacerbations
2. Pathologic fracture
3. Secondary amyloidosis
4. Endocarditis
5. Development of squamous cell carcinoma in the sinus tract (rarely osteosarcoma).

Tuberculous Osteomyelitis

Bone infection complicates up to 3% of those with pulmonary tuberculosis. Young adults or children are usually affected. The organisms usually reach the bone hematogenously. The long bones and vertebrae are favored sites. The lesions are often solitary (multifocal in AIDS patients). The infection often spreads from the initial site of bacterial deposition (the synovium of the vertebrae, hip, knee, ankle, elbow, wrist, etc) into the adjacent epiphysis, where it causes typical granulomatous inflammation with caseous necrosis and extensive
bone destruction. Tuberculosis of the vertebral bodies (Pott disease), is an important form of osteomyelitis.

Infection at this site causes vertebral deformity and collapse, with secondary neurologic deficits. Extension of the infection to the adjacent soft tissues with the development of psoas muscle abscesses is fairly common in Pott disease. Advanced cases are associated with cutaneous sinuses, which cause secondary bacterial infections. Diagnosis is established by synovial fluid direct examination, culture or PCR