Fungal
 
Superficial mycoses

1. Superficial mycoses→outermost layers of the skin or its appendages; skin, nails and/or hair.
2. Dermatophytoses transmitted by contact with man (anthropophilic; weak inflammatory response), animals (zoophilic; brisk inflammatory response), or contact with soil (geophilic; strongest inflammatory response).
3. Trichophyton→hair, skin, or nails; Microsporum → hair and skin; and Epidermophyton→skin alone.
4. The diagnosis is best made by culture of skin scrapings secured from the leading edge of the lesion.
 - use Wood's light to check for fluorescing metabolites.
 - direct KOH preparations of the scraped material
 
 Subcutaneous Mycoses
 
1. Subcutaneous mycoses are usually related to traumatic implantation into the skin.
2. Chromoblastomycosis, or verrucous (wart-like) dermatitis, is a chronic skin lesion associated with several pigmented fungi (Fonsecaea, Phialophora, and Cladosporium).
 - granulomatous reaction in subcutaneous tissue are pigmented, thick walled bodies are visible in tissue section.
3. Mycetomas (maduromycosis) are characterized by a localized, tumorous nodule (usually foot) that occurs in response to chronic progressive destruction of skin, subcutaneous tissue, fascia, muscle and bone 

4. Sporotrichosis is caused by the dimorphous fungus, Sporothrix schenckii.
 - traumatic implantation of the fungus growing in soil, thus the association with "rose gardeners disease".
 - MC lymphocutaneous disease → painless nodule at inoculation site → chain of suppurating subcutaneous nodules that drain to the skin surface along the course of the lymphatics.

- cigar shaped yeast forms are seen in the suppurative nodules and asteroid bodies (Splendore-Hoeppi phenomenon) are noted within granulomatous microabscesses.
 - treatment: oral potassium iodide

Avitaminoses -  Vitamin deficiencies are more commonly secondary disorders associated with malabsorption conditions and chronic alcoholism.

A. Vitamin A - (retinoids, fat soluble compounds derived from ß-carotene) The best-known effect of deficiency is an inability to see in weak light (night blindness due to decreased rhodopsin).
-> The pathology is also characterized by skin lesions (rash on the extremities with punctate erythematous lesions). In malnourished children, vitamin A supplements reduce the incidence of infections such as measles, even in children without signs of preexisting deficiency.

B. Vitamin D - (1, 25 OH2 D3) Deficiency produces osteomalacia (called rickets in children). Many of the effects of osteomalacia overlap with the more common osteoporosis, but the two disordersare significantly different.
-> The specific alteration in osteomalacia and rickets is a failure of mineralization of the osteoid matrix resulting in decreased appositional bone growth. 

C. Vitamin E - Very rare. Occurs as a secondary disorder in conditions associated with fat maladsorption such as cystic fibrosis, pancreatitis, and cholestasis (bile-flow obstruction).
-> Vitamin E deficiency causes a neurological disorder characterized by sensory loss, ataxia and retinitis pigmentosa due to free radical mediated neuronal damage.

D. Vitamin K - (phylloquinone) Present in most leafy plants and also synthesized by intestinal bacteria. Vitamin K is required for the production of specific clotting factors and a deficiency is characterized by impaired coagulation (elevated clotting times). Although this can occur in newborns that are given breast milk low in vitamin K, the deficiency is almost always secondarily associated with the use of certain anti-coagulants or disorders such as obstructive jaundice, celiac, or pancreatic disease.

 E. Thiamine - (B1) The deficiency is known as beriberi. Thiamine deficiency is characterized by a peripheral neuropathy that affects sensation particularly in the legs (associated with demyelination of peripheral nerves), in more severe cases Korsakoff syndrome (neuropathy characterized by impaired ocular motility, ataxia, and mental confusion) and cardiomyopathy can occur.

F. Nicotinamide (niacin) - The deficiency is known as pellagra. Primary deficiencies are associated with diets that consist primarily of a single low quality protein source (i.e. corn). It results most commonly as a complication of alcoholism.

-> The pathology is characterized by hyperkeratosis and vesiculation of skin, atrophy of the tongue epithelium, and a neuropathy that can affect cortex and peripheral neurons.

- Initial symptoms include a smooth, red tongue, a sore mouth, and ulceration of the inside of the cheeks.

- The skin on the neck, chest, and back of the hands may become brown and scaly. 

- Often there is nausea, vomiting, and diarrhea. There may also be insomnia, depression, confusion, and rapid changes of mood. Long-standing pellagra can result in dementia and death.

G. Vitamin B12 - (cobalamin) Because cobalamin is synthesized by intestinal bacteria and is widely available in many foods, deficiencies are almost always secondary disorders associated with gastric atrophy (and decreased uptake via intrinsic factor), microbial proliferation (AIDS), long-term antacids, chronic alcoholism, idiopathic (age-related).

In addition to anemia, the primary clinical symptoms include a sensory neuropathy (polyneuropathy), sclerosis of the spinal cord and atrophy of some mucous tissues.

H. Vitamin C - (ascorbic acid) The classic deficiency is known as scurvy. The essential pathology involves an inability to produce mature collagen and hence affects connective tissue.

This is characterized by an inability to synthesize osteoid and dentin (and results in decreased wound healing) and a loss of integrity of blood vessel walls.

Oral lesions are only a feature of the advanced form of the disease; early signs include fatigue, dermatitis, and purpura. There can be abnormalities in the growing bones of infants. 

I. Vitamin B6 - (Pyridoxine) A deficiency can lead to peripheral neuropathy, most commonly associated with multivitamin B deficiencies in malnutrition and alcoholism. 

V. Major Minerals - Sodium, potassium, chlorine, and magnesium are required for life but dietary deficiencies do not develop.
A. Iodine - Essential for the synthesis of thyroid hormones, and severe iodine deficiency is  associated with hypothyroidism. The compensatory activity of the thyroid gland causes a  characteristic enlargement called goiter.

B. Calcium - Required for bone mineralization, the RDA for adults is 800 mg/day. Clinical trials have shown that 1000-2000 mg/day can delay the bone loss observed in the elderly and decrease the risk of osteoporosis. See also section IV B.

VI. Trace Elements - At least 10 elements (examples: Co, Mn, Si) are required in minute amounts for normal development and metabolism.

A. Zinc - A deficiency can result from inadequate amounts given during total parenteral nutrition or as a secondary effect of acrodermatitis enteropathica (autosomal recessive trait characterized by alopecia, dermatitis, and diarrhea - the disease responds to administration of zinc).

B. Copper - Deficiencies are rare and primarily associated with malabsorption syndromes and total parenteral nutrition. Copper is required for normal hematopoiesis and bone growth. A deficiency resembles iron deficiency anemia and osteoporosis.

C. Fluoride - Levels in drinking water greater than 1 ppm cause mottling of teeth and in areas with chronic naturally induced fluorosis there is abnormal calcification of ligaments and tendons.

Cholangitis

Cholangitis is inflammation of the bile ducts. 
1. It is usually associated with biliary duct obstruction by gallstones or carcinoma, which leads to infection with enteric organisms. This results in purulent exudation within the bile ducts and bile stasis. 
2. Clinically, cholangitis presents with jaundice, fever, chills. leukocytosis, and right upper quadrant pain
 

Immunohistochemistry

 This is a method is used to detect a specific antigen in the tissue in order to identify the type of disease.

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.  
 

TUBERCULOSIS

A chronic, recurrent infection, most commonly in the lungs

Etiology, Epidemiology, and Incidence

TB refers only to disease caused by Mycobacterium tuberculosis, M. bovis, or M. africanum. Other mycobacteria cause diseases similar to TB

Pathogenesis

The stages of TB are primary or initial infection, latent or dormant infection, and recrudescent or adult-type TB.

Primary TB may become active at any age, producing clinical TB in any organ, most often the apical area of the lung but also the kidney, long bones, vertebrae, lymph nodes, and other sites. Often, activation occurs within 1 to 2 yr of initial infection, but may be delayed years or decades and activate after onset of diabetes mellitus, during periods of stress, after treatment with corticosteroids or other immunosuppressants, in adolescence, or in later life (> 70 yr of age), but especially after HIV infection. The initial infection leaves nodular scars in the apices of one or both lungs, called Simon foci, which are the most common seeds for later active TB. The frequency of activation seems unaffected by calcified scars of primary infection (Ghon foci) or by residual calcified hilar lymph nodes. Subtotal gastrectomy and silicosis also predispose to development of active TB.

Pulmonary Tuberculosis

recrudescent disease occurs in nodular scars in the apex of one or both lungs (Simon foci) and may spread through the bronchi to other portions

Recrudescence may occur while a primary focus of TB is still healing but is more often delayed until some other disease facilitates reactivation of the infection.

In an immunocompetent person whose tuberculin test is positive (>= 10 mm), exposure to TB rarely results in a new infection, because T-lymphocyte immunity controls small, exogenous inocula promptly and completely.

Symptoms and Signs:

Cough is the most common symptom,

At first, it is minimally productive of yellow or green mucus, usually on rising in the morning, but becomes more productive as the disease progresses

Dyspnea may result from rupture of the lung or from a pleural effusion caused by a vigorous inflammatory reaction

Hilar lymphadenopathy is the most common finding in children. due to lymphatic drainage from a small lesion, usually located in the best ventilated portions of the lung (lower and middle lobes), where most of the inhaled organisms are carried.

swelling of the nodes is common

Untreated infection may progress to miliary TB or tuberculous meningitis and, if long neglected, rarely may lead to pulmonary cavitation.

TB in the elderly presents special problems. Long-dormant infection may reactivate, most commonly in the lung but sometimes in the brain or a kidney, long bone, vertebra, lymph node, or anywhere that bacilli were seeded during the primary infection earlier in life

TB may develop when infection in an old calcific lymph node reactivates and leaks caseous material into a lobar or segmental bronchus, causing a pneumonia that persists despite broad-spectrum antibiotic therapy.

With HIV infection, progression to clinical TB is much more common and rapid.

HIV also reduces both inflammatory reaction and cavitation of pulmonary lesions. As a result, a patient's chest x-ray may be normal, even though AFB are present in sufficient numbers to show on a sputum smear. Recrudescent TB is almost always indicated when such an infection develops while the CD4⁺ T-lymphocyte count is >= 200/µL. By contrast, the diagnosis is usually infection by M. avium-intracellulare if the CD4+ count is < 50. The latter is noninfectious for others.

Pleural TB develops when a small subpleural pulmonary lesion ruptures, extruding caseous material into the pleural space. The most common type, serous exudate, results from rupture of a pimple-sized lesion of primary TB and contains very few organisms.

Tuberculous empyema with or without bronchopleural fistula is caused by a more massive contamination of the pleural space resulting from rupture of a large tuberculous lesion. Such a rupture allows air to escape and collapse the lung. Either type requires prompt drainage of pus and initiation of multiple drug therapy

Extrapulmonary Tuberculosis

Remote tuberculous lesions can be considered as metastases from the primary site in the lung, comparable to metastases from a primary neoplasm. TB of the tonsils, lymph nodes, abdominal organs, bones, and joints were once commonly caused by ingestion of milk infected with M. bovis.

GENITOURINARY TUBERCULOSIS

The kidney is one of the most common sites for extrapulmonary (metastatic) TB. Often after decades of dormancy, a small cortical focus may enlarge and destroy a large part of the renal parenchyma.

Salpingo-oophoritis can be a complication of primary TB after onset of menarche, when the fallopian tubes become vascular.

TUBERCULOUS MENINGITIS

Spread of TB to the subarachnoid space may occur as part of generalized dissemination through the bloodstream or from a superficial tubercle in the brain

Symptoms are fever (temperature rising to 38.3° C [101° F]), unremitting headache, nausea, and drowsiness, which may progress to stupor and coma. Stiff neck (Brudzinski's sign) and straight leg raising are inconstant but are helpful signs, if present. Stages of tuberculous meningitis are (1) clear sensorium with abnormal CSF, (2) drowsiness or stupor with focal neurologic signs, and (3) coma. Likelihood that CNS defects will become permanent increases with the stage. Symptoms may progress suddenly if the lesion causes thrombosis of a major cerebral vessel.

Diagnosis is made by examining CSF. The most helpful CSF findings include a glucose level < 1/2 that in the serum and an elevated protein level along with a pleocytosis, largely of lymphocytes. Examination of CSF by PCR is most helpful, rapid, and highly specific.

MILIARY TUBERCULOSIS

When a tuberculous lesion leaks into a blood vessel, massive dissemination of organisms may occur, causing millions of 1- to 3-mm metastatic lesions. Such spread, named miliary because the lesions resemble millet seeds, is most common in children < 4 yr and in the elderly.

TUBERCULOUS LYMPHADENITIS

In primary infection with M. tuberculosis, the infection spreads from the infected site in the lung to the hilar nodes. If the inoculum is not too large, other nodes generally are not involved. However, if the infection is not controlled, other nodes in the superior mediastinum may become involved. If organisms reach the thoracic duct, general dissemination may occur. From the supraclavicular area, nodes in the anterior cervical chain may be inoculated, thus sowing the seeds for tuberculous lymphadenitis at a later time. Most infected nodes heal, but the organisms may lie dormant and viable for years or decades and can again multiply and produce active disease.