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

Characteristics of Immunoglobulin subclasses

I. Ig G:

(i) Predominant portion (80%) of Ig.

(ii) Molecular weight 150, 000

(iii) Sedimentation coefficient of 7S.

(iv) Crosses placental barrier and to extra cellular fluid.

• (v) Mostly neutralising effect. May be complement fixing.

(vi) Half life of 23 days.

2.IgM :

(i) Pentamer of Ig.

(ii) Molecular weight 900, 000

(iii) 19S.

(iv) More effective complement fixation and cells lysis

(v) Earliest to be produced in infections.

(vi) Does not cross placental barrier.

(vii) Halflife of 5 days.

3. Ig A :

• Secretory  antibody. Found in intestinal, respiratory secretions tears, saliva and urine also.
• Secreted  usually as a dinner with secretory piece.
• Mol. weight variable (160,000+)
• 7 S to 14 S.
• Half life of 6 days.

4.Ig D :

• Found in traces.
• 7 S.
• Does not cross placenta.

5. Ig E

• Normally not traceable
• 7-8 S (MoL weight 200,000)
• Cytophilic antibody, responsible for some hypersensitivity states,

Nephrotic Syndrome
The patient will present with a triad of symptoms:
- Proteinuria, i.e. >3g/24hr-3.5g/24 hr
- Hypoalbuminaemia, i.e. <30g/L
- Oedema 
 >80% of cases are due to glomerulonephritis. In this syndrome, there is damage to podocytes 
 
 Clinical signs
- Pitting oedema, particularly in the limbs and around the eyes; may also cause genital oedema and ascites.
- Possible hypertension 

Causes
- Primary causes – these are diagnoses of exclusion that are only made if secondary causes cannot be found
    o Minimal change disease (MCD)
    o Focal segmental glomerulosclerosis
    o Membranous nephropathy
- Secondary causes – note that these fall into the same three categories as above:
    o Minimal change disease – Hep B, SLE, diabetes M, sarcoidosis, syphilis, malignancy
    o Focal segmental glomerulosclerosis –HIV, obesity, diabetes M, hypertensive nephrosclerosis
    o Minimal change disease –drugs, malignancy, particularly Hodgkin’s lymphoma  
    
 - Differential diagnoses include cardiac failure, i.e. increased JVP, pulmonary oedema and mild proteinuria, and liver disease, i.e. reduced serum albumin.
- The condition causes an increased susceptibility to infection – partly due to loss of immunoglobulin in the urine. Patients tend to be prone to streptococcus infection, as well as bacterial peritonitis and cellulitis.
- Nephrotic syndrome also increases the risk of thromboembolism and hyperlipidaemia.
- The former is due to an increase in the synthesis of clotting factors and to platelet abnormalities, and the latter is a result of increased synthesis of these by the liver to counteract reduced oncotic pressure.  

Investigations

- These are the same as those carried out in GN.
- Also, check for cholesterol as part of confirming the presence of hyperlipidemia.
- Renal biopsy – order this for all adults. In children, because the main cause is minimal change GN, steroids are the first-line treatment. Therefore, in children, biopsy is necessary only if pharmaceutical intervention fails to improve the situation.
- The hypercoagulant state seen in the nephrotic syndrome can be a risk factor for renal vein thrombosis. This can present as loin pain, haematuria, palpable kidney and sudden deterioration in kidney function. This should be investigated with Doppler USS, MRI or even renal angiography.
- Once diagnosed, give warfarin for 3 to 6 months.

Management

- Generally, this involves treatment of the underlying condition which is usually GN. Therefore, fluid management and salt intake restriction are priorities. The patient is usually given furosemide along with an ACE inhibitor and/or an angiotensin II receptor antagonist. Prophylactic heparin is given if the patient is immobile. Hyperlipidaemia can be treated with a statin. 

Nephritic Syndrome 

Acute and chronic
forms of the syndrome exist. The main difference between this and nephrotic syndrome is that in nephritic syndrome haematuria is present. There is also proteinuria, hypertension, uraemia, and possibly oliguria. The two standout features are hypertension and RBC casts. The urine will often appear ‘smoky’ in colour due to the presence of RBC casts. Very rarely, it may appear red 

Causes

1. Post-streptococcal
2. Primary:
- Membranous glomerulonephritis
- Rapidly progressive glomerulonephritis
- IgA nephropathy (Berger’s disease)
3. Secondary
- HSP
- Vasculitis

Clinical Features

- Abrupt onset of :
    o Glomerular haematuria (RBC casts or dysmorphic RBC)
    o Non-nephrotic range proteinuria (< 2 g in 24 hrs)
    o Oedema (periorbital, sacral )
    o Hypertension
    o Transient renal impairment (oliguria, uraemia)
- Urinary casts – these are cylindrical structures produced by the kidney and present in the urine in certain renal diseases. They form in the DCT and collecting duct, dislodging and passing in the urine where they are detected by microscopy. RBC casts are usually associated with nephritic syndrome. The presence of RBCs within a cast is always pathologic and strongly indicative of glomerular damage.
- The proteinuria present is often smaller than in nephrotic syndrome, thus a coexistent condition of nephrotic syndrome is not usually present.
- Encepelopathy may be present, particularly in children, due to electrolyte imbalances and hypertension. This type of presentation is indicative of glomerular damage, but requires renal biopsy to determine the exact problem. In this respect it is similar to nephrotic syndrome.
Overlapping of the two syndromes is possible as nephrotic syndrome may precede nephritic syndrome, although not vice-versa.

Mechanisms of the syndrome vary according to cause; both primary and secondary causes exist. Post-infectious GN is the classic illustration of nephritic syndrome, but the condition may be caused by other glomerulopathies and by systemic diseases such as connective tissue disorders 

Two clinical terms to remember:
- Nephritic syndrome; which comprises edema, proteinuria, hypoalbuminemia, hematuria (smoky urine), oligurua and hypertension.
- Nephrotic syndrome; which comprises of albuminuria, hypoalbuminemia, edema, hyperlipidemia, lipiduria. 

ADRENAL INSUFFICIENCY

Adrenocortical hypofunction is either primary (adrenocrtical) or secondary (ACTH deficiency). Primary insufficiency is divided into acute & chronic. 
Acute Adrenocortical Insufficiency occurs most commonly in the following clinical settings
- massive adrenal hemorrhage including  Waterhouse-Friderichsen syndrome 
- Sudden withdrawal of long-term corticosteroid therapy
- Stress in those with chronic adrenal insufficiency 

Massive adrenal hemorrhage may destroy the adrenal cortex sufficiently to cause acute adrenocortical 
insufficiency. This condition may occur 
1. in patients maintained on anticoagulant therapy 
2. in postoperative patients who develop DIC
3. during pregnancy 
4. in patients suffering from overwhelming sepsis (Waterhouse-Friderichsen syndrome) 

Waterhouse-Friderichsen syndrome is a catastrophic syndrome classically associated with Neisseria meningitidis septicemia but can also be caused by other organisms, including Pseudomonas species, pneumococci & Haemophilus influenzae. The pathogenesis of the syndrome remains unclear, but probably involves endotoxin-induced vascular injury with associated DIC.

Chronic adrenocortical insufficiency (Addison disease) results from progressive destruction of the adrenal cortex. More than 90% of all cases are attributable to one of four disorders: 
1. autoimmune adrenalitis (the most common cause; 70% of cases) 
2. tuberculosis &fungal infections 
3. AIDS
4. Metastatic cancers   
In such primary diseases, there is hyperpigmentation of the skin oral mucosa due to high levels of MSH (associated with high levels of ACTH).

Autoimmune adrenalitis is due to autoimmune destruction of steroid-producing cells. It is either isolated associated other autoimmune diseases, such as Hashimoto disease, pernicious anemia, etc. 

Infections, particularly tuberculous and fungal

Tuberculous adrenalitis, which once was responsible for as many as 90% of cases of Addison disease, has become less common with the advent of antituberculous therapy. When present, tuberculous adrenalitis is usually associated with active infection elsewhere, particularly the lungs and genitourinary tract. Among fungi, disseminated infections caused by Histoplasma capsulatum is the main cause. 

AIDS patients are at risk for developing adrenal insufficiency from several infectious (cytomegalovirus, Mycobacterium avium-intracellulare) and noninfectious (Kaposi sarcoma) complications.
 
Metastatic neoplasms: the adrenals are a fairly common site for metastases in persons with disseminated carcinomas. Although adrenal function is preserved in most such patients, the metastatic growths sometimes destroy sufficient adrenal cortex to produce a degree of adrenal insufficiency. Carcinomas of the lung and breast are the major primary sources. 

Secondary Adrenocortical Insufficiency

Any disorder of the hypothalamus and pituitary, such as metastatic cancer, infection, infarction, or irradiation, that reduces the output of ACTH leads to a syndrome of hypoadrenalism having many similarities to Addison disease. In such secondary disease, the hyperpigmentation of primary Addison disease is lacking because melanotropic hormone levels are low. 

Secondary adrenocortical insufficiency is characterized by low serum ACTH and a prompt rise in plasma cortisol levels in response to ACTH administration. 

Pathological features of adrenocortical deficiency 

- The appearance of the adrenal glands varies with the cause of the insufficiency. 
- In secondary hypoadrenalism the adrenals are reduced to small, uniform, thin rim of atrophic yellow cortex that surrounds a central, intact medulla. Histologically, there is atrophy of cortical cells with loss of cytoplasmic lipid, particularly in the zonae fasciculata and reticularis. 
- In primary autoimmune adrenalitis there is also atrophy of the cortex associated with a variable lymphoid infiltrate that may extend into the subjacent medulla. The medulla is otherwise normal.  
- In tuberculosis or fungal diseases there is granulomatous inflammatory reaction. Demonstration of the responsible organism may require the use of special stains.  
- With metastatic carcinoma, the adrenals are enlarged and their normal architecture is obscured by the infiltrating neoplasm.  
 

Bronchiectasis 
- Bronchiectasis is abnormal and irreversible dilatation of the bronchi and bronchioles (greater than 2 mm in diameter) secondary to inflammatory weakening of bronchial wall.
- Occur in childhood and early adult life
- Persistent cough with copious amount of foul smelling purulent sputum

Aetiopathogenesis
Bronchial wall destruction is due to:
- Endobronchial obstruction due to foreign body
- Infection due to local obstruction or impaired defence mechanism 

Clinical conditions:
- Hereditary and congenital factors
- Obstruction
- Secondary complication

Hereditary and congenital factors:
- Congenital bronchiectasis due to developmental defects
- Cystic fibrosis causing defective secretion resulting in obstruction
- Hereditary immune defiency diseases
- Immotile cilia syndrome- immotile cilia of respiratory tract, sperms causing Kartagener’s syndrome (bronchiectasis, situs inversus and sinusitis) and male infertility
- Allergic bronchial asthma patients

Obstruction:

Localised variety in one part of bronchial system.
Obstruction can be due to
Foreign body
Endobronchial tumors
Hilar lymph nodes
Inflammatory scarring (TB)

Secondary complication:

Necrotizing pneumonia in Staph infection and TB

Morphologic changes

- Affects distal bronchi and bronchioles
- Lower lobes more frequently
- Lungs involved diffusely/segmentally
- Left lower lobe than right
- Pleura fibrotic & thickened adherent to chest wall

C/S lung: Honey-combed appearance

Microscopic examination:
Bronchiole-dilated
Bronchial epithelium-normal, ulcerated, squamous metaplasia
Bronchial wall-infiltration by ac & Ch inflammatory cells,
destruction of muscle, elastic tissue 
Lung parenchyma-fibrosis, surrounding tissue pneumonia
Pleura-fibrotic and adherent

Bullous and Vesicular Disease
1. There are many diseases characterized by the presence of vesicles and bullae filled  fluid.
2. In pemphigus vulgaris, large, flaccid bullae filled with fluid occur on the skin and within the oral mucosa.
 - immunologic disease with IgG antibodies against the intercellular attachment sites between keratinocytes (type II hypersensitivity).
 - the vesicle in pemphigus vulgaris has a suprabasal location (just above the basal cell layer and resembling "tombstones")
 - scattered keratinocytes in the fluid as a result of acantholysis.
 - Nikolsky's sign is where the epidermis slips when touched with the finger.
 - fatal disease if left untreated (systemic corticosteroids)
3. Bullous pemphigoid is an immunologic vesicular disease whose vesicle are in a subepidermal location.
 - circulating IgG antibody against antigens in the basement membrane (type II hypersensitivity).
4. Dermatitis herpetiformis is an immunologic vesicular lesion characterized by the presence of IgA immune complexes (type III hypersensitivity) at the tips of the dermal papilla at the dermal/epidermal junction producing a subepidermal vesicle filled with neutrophils.
 - strong association with gluten-sensitive enteropathy, or celiac disease.