It is a classic example of delayed It is a classic example of delayed hypersensitivity.hypersensitivity.

The The tuberculin reactiontuberculin reaction, is , is produced by the intracutaneous produced by the intracutaneous injection of tuberculin, a protein-injection of tuberculin, a protein-lipopolysaccharide component of lipopolysaccharide component of the tubercle bacillus. the tubercle bacillus.

In a previously sensitized individual, In a previously sensitized individual, reddening and induration of the site reddening and induration of the site appear in 8 to 12 hours, reach a peak in appear in 8 to 12 hours, reach a peak in 24 to 72 hours, and thereafter slowly 24 to 72 hours, and thereafter slowly subside. subside.

Morphologically, delayed type Morphologically, delayed type hypersensitivity is characterized by the hypersensitivity is characterized by the accumulation of mononuclear cells accumulation of mononuclear cells around small veins and venules, around small veins and venules, producing a perivascular "cuffing" .producing a perivascular "cuffing" .

Plasma proteins escape, giving rise to Plasma proteins escape, giving rise to dermal edema and deposition of fibrin in dermal edema and deposition of fibrin in the interstitium.the interstitium.

The latter appears to be the main cause The latter appears to be the main cause of induration, which is characteristic of of induration, which is characteristic of delayed hypersensitivity skin lesions.delayed hypersensitivity skin lesions.

In fully developed lesions, the In fully developed lesions, the lymphocyte-cuffed venules show marked lymphocyte-cuffed venules show marked endothelial hypertrophy and, in some endothelial hypertrophy and, in some cases, hyperplasia. cases, hyperplasia.

Leprosy/Hansen Leprosy/Hansen

diseasedisease

M. lepraeM. leprae is an acid-fast obligate is an acid-fast obligate intracellular organism that grows intracellular organism that grows very poorly in culture. very poorly in culture.

It grows more slowly than other It grows more slowly than other mycobacteria and grows best at mycobacteria and grows best at 32° to 34°C, the temperature of 32° to 34°C, the temperature of the human skinthe human skin

Is a slowly progressive infection Is a slowly progressive infection caused by caused by Mycobacterium lepraeMycobacterium leprae, , affecting the skin and peripheral affecting the skin and peripheral nerves and resulting in disabling nerves and resulting in disabling deformities.deformities.

M. lepraeM. leprae is likely to be transmitted is likely to be transmitted from person to person through from person to person through aerosols from lesions in the upper aerosols from lesions in the upper respiratory tract. respiratory tract.

Inhaled Inhaled M. lepraeM. leprae, like , like M. M. tuberculosistuberculosis, is taken up by alveolar , is taken up by alveolar macrophages and disseminates macrophages and disseminates through the blood, but grows only in through the blood, but grows only in tissues of the skin and extremities. tissues of the skin and extremities.

leprosy remains endemic among an leprosy remains endemic among an estimated 10 to 15 million people estimated 10 to 15 million people living in poor tropical countriesliving in poor tropical countries

Like Like M. tuberculosisM. tuberculosis, , M. lepraeM. leprae secretes no toxins, and its secretes no toxins, and its virulence is based on properties virulence is based on properties of its cell wall. of its cell wall.

The cell wall is similar enough to The cell wall is similar enough to that of that of M. tuberculosis.M. tuberculosis.

Cell-mediated immunity is Cell-mediated immunity is reflected by delayed type reflected by delayed type hypersensitivity reactions to hypersensitivity reactions to dermal injections of a bacterial dermal injections of a bacterial extract called extract called leprominlepromin

Leprosy has two strikingly Leprosy has two strikingly different patterns of diseasedifferent patterns of disease..

Tuberculoid leprosyTuberculoid leprosy, , Lepromatous leprosyLepromatous leprosy

TTuberculoid leprosyuberculoid leprosy

1)1) LLess severe form, ess severe form,

2)2) have dry, scaly skin lesions that have dry, scaly skin lesions that lack sensation. lack sensation.

3)3) They often have large, They often have large, asymmetric peripheral nerve asymmetric peripheral nerve involvement. involvement.

Begins with small localized skin Begins with small localized skin lesions that are first flat and red lesions that are first flat and red but enlarge and develop but enlarge and develop irregular shapes with indurated, irregular shapes with indurated, elevated, hyperpigmented elevated, hyperpigmented margins and depressed pale margins and depressed pale centers (central healing). centers (central healing).

On microscopic examination, all On microscopic examination, all sites of involvement disclose sites of involvement disclose granulomatous lesions closely granulomatous lesions closely resembling those found in resembling those found in tuberculosis, and bacilli are almost tuberculosis, and bacilli are almost never found. never found.

The presence of granulomas and The presence of granulomas and absence of bacteria reflect strong T-absence of bacteria reflect strong T-cell immunity. cell immunity.

lepromatous leprosylepromatous leprosy,,

The more severe form of leprosy, The more severe form of leprosy,

includes symmetric skin includes symmetric skin thickening and nodules. thickening and nodules.

This is also called This is also called anergic leprosyanergic leprosy, , because of the unresponsiveness because of the unresponsiveness (anergy) of the host immune (anergy) of the host immune system. system.

In lepromatous leprosy, damage to the In lepromatous leprosy, damage to the nervous system comes from nervous system comes from widespread invasion of the widespread invasion of the mycobacteria into Schwann cells and mycobacteria into Schwann cells and into endoneural and perineural into endoneural and perineural macrophages. macrophages.

- In advanced cases of lepromatous - In advanced cases of lepromatous leprosy, leprosy, M. lepraeM. leprae is present in is present in sputum and blood. sputum and blood.

3- People can also have 3- People can also have intermediate forms of disease, intermediate forms of disease, called called borderline leprosyborderline leprosy. .

Contractures, paralyses, and Contractures, paralyses, and autoamputation of fingers or toes autoamputation of fingers or toes may ensue. may ensue.

Facial nerve involvement can lead Facial nerve involvement can lead to paralysis of the eyelids, with to paralysis of the eyelids, with keratitis and corneal ulcerations. keratitis and corneal ulcerations.

Figure 8-31 The morphologic spectrum of tuberculosis. A characteristic tubercle at low magnification (A) and in detail (B) illustrates central caseation surrounded by epithelioid and multinucleated giant cells. This is the usual response seen in patients who have developed cell mediated immunity to the organism. Occasionally, even in immunocompetent individuals, tubercular granulomas might not show central caseation (C); hence, irrespective of the presence or absence of caseous necrosis, special stains for acid-fast organisms need to be performed when granulomas are present in histologic section. In immunosuppressed individuals, tuberculosis may not elicit a

granulomatous response ("nonreactive tuberculosis"); instead, sheets of foamy histiocytes are seen, packed with mycobacteria that are demonstrable with acid-fast stains (D). (D, Courtesy of Dr. Dominick Cavuoti, Department of Pathology, University of Texas Southwestern Medical School, Dallas, TX.)

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© 2005 Elsevier

M. lepraeM. leprae is an acid-fast obligate is an acid-fast obligate intracellular organism that grows intracellular organism that grows very poorly in culture. very poorly in culture.

It grows more slowly than other It grows more slowly than other mycobacteria and grows best at mycobacteria and grows best at 32° to 34°C, the temperature of 32° to 34°C, the temperature of the human skin.the human skin.

Morphology of Lepromatous Morphology of Lepromatous leprosyleprosy

Lepromatous lesions contain large Lepromatous lesions contain large aggregates of lipid-laden macrophages aggregates of lipid-laden macrophages (lepra cells), often filled with masses of (lepra cells), often filled with masses of acid-fast bacilli (globi). acid-fast bacilli (globi).

No granulomas are formed and it No granulomas are formed and it reflects failure of the immune response.reflects failure of the immune response.

Nodules/protuberances are formed, may Nodules/protuberances are formed, may give rise to Leonine like faces. give rise to Leonine like faces.

Morphology of Lepromatous Morphology of Lepromatous leprosyleprosy Macular, papular, or nodular lesions form on Macular, papular, or nodular lesions form on

the face, ears, wrists, elbows, and knees.the face, ears, wrists, elbows, and knees. With progression, the nodular lesions With progression, the nodular lesions

coalesce to yield a distinctive leonine coalesce to yield a distinctive leonine facies. facies.

Most skin lesions are hypoesthetic or Most skin lesions are hypoesthetic or anesthetic. Lesions in the nose may cause anesthetic. Lesions in the nose may cause persistent inflammation and bacilli-laden persistent inflammation and bacilli-laden discharge.discharge.

Nodular lesions of the face may coalesce to Nodular lesions of the face may coalesce to produce a lion-like appearance (leonine produce a lion-like appearance (leonine facies). facies).

3- People can also have 3- People can also have intermediate forms of disease, intermediate forms of disease, called called borderline leprosyborderline leprosy. .

Lymph nodes show aggregation of foamy Lymph nodes show aggregation of foamy macrophages in the paracortical (T-cell) macrophages in the paracortical (T-cell) areas, with enlargement of germinal areas, with enlargement of germinal centers. centers.

In advanced disease, aggregates of In advanced disease, aggregates of macrophages are also present in the macrophages are also present in the splenic red pulp and the liver. splenic red pulp and the liver.

The testes are usually extensively The testes are usually extensively involved, with destruction of the involved, with destruction of the seminiferous tubules and consequent seminiferous tubules and consequent sterility. sterility.

DiagnosisDiagnosis

Skin biopsy, scraping of lesions or Skin biopsy, scraping of lesions or nasal smears.nasal smears.

Use of acid fast Fite Stain: it will stain Use of acid fast Fite Stain: it will stain the bacteria pink/red.the bacteria pink/red.

Lepromin test.Lepromin test. Rapid Method by measuring Rapid Method by measuring

Antibodies to the M.Leprae.Antibodies to the M.Leprae. Nerve Bx.,EMG diagnosis of leprosy.Nerve Bx.,EMG diagnosis of leprosy. PCRPCR

TreatmentTreatment

Multidrug antileprosy medication.Multidrug antileprosy medication. With adequate treatment With adequate treatment

prognosis is excellent.prognosis is excellent.

SchistosomiasisSchistosomiasis

Schistosomiasis infects approximately Schistosomiasis infects approximately 200 million persons and kills 200 million persons and kills approximately 280,000 annually. approximately 280,000 annually.

Schistosoma mansoniSchistosoma mansoni in Latin America, in Latin America, Africa, and the Middle East Africa, and the Middle East

Schistosoma japonicumSchistosoma japonicum and and Schistosoma Schistosoma mekongimekongi in East Asia. in East Asia.

Schistosoma haematobiumSchistosoma haematobium, found in , found in Africa, causes hematuria and Africa, causes hematuria and granulomatous disease of the bladder, granulomatous disease of the bladder, resulting in chronic obstructive uropathy. resulting in chronic obstructive uropathy.

Pathogenesis/Life CyclePathogenesis/Life Cycle

Schistosomiasis is transmitted by Schistosomiasis is transmitted by freshwater snails that live in the slow-freshwater snails that live in the slow-moving water of tropical rivers, lakes, moving water of tropical rivers, lakes, and irrigation ditches, ironically linking and irrigation ditches, ironically linking agricultural development with spread of agricultural development with spread of the disease. the disease.

Infectious schistosome larvae (cercariae) Infectious schistosome larvae (cercariae) swim through fresh water and penetrate swim through fresh water and penetrate human skin with the aid of powerful human skin with the aid of powerful proteolytic enzymes that degrade the proteolytic enzymes that degrade the keratinized layer. keratinized layer.

Within the skin, schistosome Within the skin, schistosome larvae shed a surface glycocalyx larvae shed a surface glycocalyx that protects the organisms from that protects the organisms from osmotic shock. osmotic shock.

Life cycleLife cycle

Schistosomes migrate into the Schistosomes migrate into the peripheral vasculature, settle in peripheral vasculature, settle in the portal or pelvic venous the portal or pelvic venous system, where they develop into system, where they develop into adult male and female adult male and female schistosomes. schistosomes.

Females produce hundreds of Females produce hundreds of eggs per day, around which eggs per day, around which granulomas and fibrosis form. granulomas and fibrosis form.

Life cycleLife cycle

Some schistosome eggs are Some schistosome eggs are passed from the portal veins passed from the portal veins through the intestinal wall into through the intestinal wall into the colonic lumen, are shed with the colonic lumen, are shed with the feces, and release into the feces, and release into freshwater miracidia that infect freshwater miracidia that infect the snails to complete the life the snails to complete the life cycle. cycle.

In mildIn mild S. mansoniS. mansoni oror S. japonicumS. japonicum infectionsinfections, white, pinhead-sized granulomas , white, pinhead-sized granulomas are scattered throughout the gut and liver.are scattered throughout the gut and liver.

At the center of the granuloma is the At the center of the granuloma is the schistosome egg, this degenerates over time schistosome egg, this degenerates over time and calcifies. and calcifies.

The granulomas are composed of The granulomas are composed of macrophages, lymphocytes, neutrophils, and macrophages, lymphocytes, neutrophils, and eosinophils.eosinophils.

The liver is darkened by pigments from the The liver is darkened by pigments from the schistosome gut.schistosome gut.

In severeIn severe S. mansoniS. mansoni oror S. S. japonicumjaponicum infectionsinfections, , inflammatory patches or inflammatory patches or pseudopolyps may form in the colon. pseudopolyps may form in the colon.

The surface of the liver is bumpy, The surface of the liver is bumpy, whereas cut surfaces reveal whereas cut surfaces reveal granulomas and a widespread fibrous granulomas and a widespread fibrous portal enlargement without distortion portal enlargement without distortion of the intervening parenchyma by of the intervening parenchyma by regenerative nodules. regenerative nodules.

Because these fibrous triads Because these fibrous triads resemble the stem of a clay pipe, resemble the stem of a clay pipe, the lesion is named the lesion is named pipe-stem pipe-stem fibrosisfibrosis. .

This results in the development of This results in the development of portal hypertension and severe portal hypertension and severe congestive splenomegaly, congestive splenomegaly, esophageal varices, and ascites. esophageal varices, and ascites.

Schistosome mansoni and Schistosome mansoni and japonicum eggs, diverted to the japonicum eggs, diverted to the lung through portal collaterals, lung through portal collaterals, may produce granulomatous may produce granulomatous pulmonary arteritis with intimal pulmonary arteritis with intimal hyperplasia, progressive arterial hyperplasia, progressive arterial obstruction, and ultimately heart obstruction, and ultimately heart failure (cor pulmonale).failure (cor pulmonale).

On histologic examination, On histologic examination, arteries in the lungs show arteries in the lungs show disruption of the elastica layer by disruption of the elastica layer by granulomas and scars, luminal granulomas and scars, luminal organizing thrombi, and organizing thrombi, and angiomatoid lesions similar to angiomatoid lesions similar to those of idiopathic pulmonary those of idiopathic pulmonary hypertensionhypertension

InIn S. haematobiumS. haematobium infectioninfection, , bladder inflammatory patches due to bladder inflammatory patches due to massive egg deposition and massive egg deposition and granulomas appear early, and when granulomas appear early, and when they erode, they cause hematuria.they erode, they cause hematuria.

Later, the granulomas calcify and Later, the granulomas calcify and develop a "sandy" appearance, develop a "sandy" appearance, which, if severe, may line the wall of which, if severe, may line the wall of the bladder and cause a dense the bladder and cause a dense concentric rim (calcified bladder) on concentric rim (calcified bladder) on radiographic films. radiographic films.

The most frequent complication The most frequent complication of of S. haematobiumS. haematobium infection is infection is inflammation and fibrosis of the inflammation and fibrosis of the ureteral walls, leading to ureteral walls, leading to obstruction, hydronephrosis, and obstruction, hydronephrosis, and chronic pyelonephritis. chronic pyelonephritis.

There is also an association There is also an association between urinary schistosomiasis between urinary schistosomiasis and squamous cell carcinoma of and squamous cell carcinoma of the bladder. the bladder.

SarcoidosisSarcoidosis

Is a systemic disease of unknown cause Is a systemic disease of unknown cause characterized by noncaseating characterized by noncaseating granulomas in many tissues and organs.granulomas in many tissues and organs.

Somme studies have suggested possible Somme studies have suggested possible role of M.TB &Proprionibacterium. role of M.TB &Proprionibacterium.

Bilateral hilar lymphadenopathy or lung Bilateral hilar lymphadenopathy or lung involvement is visible on chest involvement is visible on chest radiographs in 90% of cases. radiographs in 90% of cases.

. .

Eye and skin lesions are next in Eye and skin lesions are next in frequencyfrequency

SarcoidosisSarcoidosis

histologic diagnosis of sarcoidosis is histologic diagnosis of sarcoidosis is made by exclusionmade by exclusion

The prevalence of sarcoidosis is higher in The prevalence of sarcoidosis is higher in women and in American blacks than in women and in American blacks than in whites. whites.

Although the etiology of sarcoidosis Although the etiology of sarcoidosis remains unknown, evidence suggest that remains unknown, evidence suggest that it is a disease of disordered immune it is a disease of disordered immune regulation in genetically predisposed regulation in genetically predisposed individuals exposed to certain individuals exposed to certain environmental agentsenvironmental agents

SarcoidosisSarcoidosis

Histologically, all involved tissues Histologically, all involved tissues show the classic show the classic noncaseating noncaseating granulomasgranulomas, each composed of an , each composed of an aggregate of tightly clustered aggregate of tightly clustered epithelioid cells. epithelioid cells.

With chronicity, the granulomas may With chronicity, the granulomas may become enclosed within fibrous rims become enclosed within fibrous rims or may eventually be replaced by or may eventually be replaced by hyaline fibrous scars. hyaline fibrous scars.

Two other microscopic features are often Two other microscopic features are often present in the granulomas: present in the granulomas:

(1)(1)laminated concretions composed of laminated concretions composed of calcium and proteins known as calcium and proteins known as Schaumann bodies anSchaumann bodies an

(2)(2)(2) stellate inclusions known as asteroid (2) stellate inclusions known as asteroid bodies enclosed within giant cells found bodies enclosed within giant cells found in approximately 60% of the granulomas. in approximately 60% of the granulomas.

Pathologic involvement of virtually every Pathologic involvement of virtually every organ in the body has been cited at one organ in the body has been cited at one time or another. time or another.

The The lungslungs are common sites of are common sites of involvement.involvement.

Macroscopically, there is usually no Macroscopically, there is usually no demonstrable alteration, although at demonstrable alteration, although at times, the coalescence of granulomas times, the coalescence of granulomas may produce small nodules that are may produce small nodules that are palpable or visible as 1- to 2-cm, palpable or visible as 1- to 2-cm, noncaseating, noncavitated noncaseating, noncavitated consolidations. consolidations.

The granulomas are seen in the The granulomas are seen in the bronchial submucosa and with bronchial submucosa and with healing fibrosis and hyalinization healing fibrosis and hyalinization are often found. are often found.

The pleural surfaces are The pleural surfaces are sometimes involved. sometimes involved.

The The spleenspleen is affected microscopically in is affected microscopically in about three quarters of cases, but it is about three quarters of cases, but it is enlarged in only one fifth. On occasion, enlarged in only one fifth. On occasion, granulomas may coalesce to form small granulomas may coalesce to form small nodules that are barely visible nodules that are barely visible macroscopically. The capsule is not involved.macroscopically. The capsule is not involved.

The The liverliver is affected slightly less often than is affected slightly less often than

the spleen. It may also be moderately the spleen. It may also be moderately enlarged and may contain scattered enlarged and may contain scattered granulomas, more in portal triads than in the granulomas, more in portal triads than in the lobular parenchyma. Needle biopsy may lobular parenchyma. Needle biopsy may permit the identification of these focal lesions.permit the identification of these focal lesions.

The The bone marrowbone marrow is an additional is an additional favoured site of localization.favoured site of localization.

Skin lesionsSkin lesions are encountered in one are encountered in one third to one half of cases. Sarcoidosis third to one half of cases. Sarcoidosis of the skin assumes a variety of of the skin assumes a variety of macroscopic appearancesmacroscopic appearances

e.g., discrete subcutaneous nodules;e.g., discrete subcutaneous nodules; focal, slightly elevated, focal, slightly elevated,

erythematous plaques; erythematous plaques;

or flat lesions that are slightly or flat lesions that are slightly reddened and scaling and reddened and scaling and resemble those of lupus resemble those of lupus erythematosuserythematosus

Lesions may also appear on the Lesions may also appear on the mucous membranes of the oral mucous membranes of the oral cavity, larynx, and upper respiratory cavity, larynx, and upper respiratory tract. tract.

Bilateral sarcoidosis of the parotid, Bilateral sarcoidosis of the parotid, submaxillary, and sublingual glands submaxillary, and sublingual glands completes the combined uveoparotid completes the combined uveoparotid involvement designated as involvement designated as Mikulicz Mikulicz syndrome.syndrome.

The The eye, its associated glands, eye, its associated glands, and the salivary glandsand the salivary glands are are involved in about one fifth to one involved in about one fifth to one half of cases. half of cases.

The The ocular involvementocular involvement takes the takes the form of iritis or iridocyclitis, either form of iritis or iridocyclitis, either bilaterally or unilaterally. bilaterally or unilaterally. Consequently, corneal opacities, Consequently, corneal opacities, glaucoma, and total loss of vision glaucoma, and total loss of vision may occur. These ocular lesions are may occur. These ocular lesions are frequently accompanied by frequently accompanied by inflammation of the lacrimal glands, inflammation of the lacrimal glands, with suppression of lacrimation. with suppression of lacrimation.

MuscleMuscle involvement may be involvement may be asymptomatic or symptomaticasymptomatic or symptomatic

muscle weakness, aches, muscle weakness, aches, tenderness, and fatigue. tenderness, and fatigue.

In one study, 22 patients In one study, 22 patients presenting withpresenting with

Sarcoidosis may be discovered Sarcoidosis may be discovered unexpectedly on routine chest unexpectedly on routine chest films as bilateral hilar adenopathy films as bilateral hilar adenopathy or may present with peripheral or may present with peripheral lymphadenopathy, cutaneous lymphadenopathy, cutaneous lesions, eye involvement, lesions, eye involvement, splenomegaly, or hepatomegaly. splenomegaly, or hepatomegaly.

Hypercalcemia, hypergamma-Hypercalcemia, hypergamma-globulinemia and hypercalciuria.globulinemia and hypercalciuria.

In the great majority of cases, however, In the great majority of cases, however, patients seek medical attention because patients seek medical attention because of the insidious onset of respiratory of the insidious onset of respiratory abnormalities (shortness of breath, abnormalities (shortness of breath, cough, chest pain, hemoptysis) or of cough, chest pain, hemoptysis) or of constitutional signs and symptoms constitutional signs and symptoms (fever, fatigue, weight loss, anorexia, (fever, fatigue, weight loss, anorexia, night sweats). night sweats).

Some die of cardiac or central Some die of cardiac or central nervous system damage, but nervous system damage, but most succumb to progressive most succumb to progressive pulmonary fibrosis and cor pulmonary fibrosis and cor pulmonale. pulmonale.

DIAGNOSISDIAGNOSIS

For a typical case diagnosis is made by aFor a typical case diagnosis is made by a combination of clinical,radoigraphic and combination of clinical,radoigraphic and

histological findings.histological findings. The Kviem-Siltzback skin test consists of The Kviem-Siltzback skin test consists of

the intradermal injection of a heat treated the intradermal injection of a heat treated suspension of a sarcoidosis spleen extract suspension of a sarcoidosis spleen extract which is biopsied 4 to 6 weeks later, yeilds which is biopsied 4 to 6 weeks later, yeilds sarcoidosis like lesions in80% of individuals sarcoidosis like lesions in80% of individuals with sarcoidosis.with sarcoidosis.

Other investigations: chest x-ray, estimation Other investigations: chest x-ray, estimation of calcium and globulin levels in blood, of calcium and globulin levels in blood, biopsy of affected organs.biopsy of affected organs.

Treatment is with corticosteroids and Treatment is with corticosteroids and prognosis is generally good.prognosis is generally good.

LeishmaniasisLeishmaniasis