Granulomatous Inflammation

Granulomatous diseases OBJECTIVESDEFINITIONCAUSESTYPES PATHOGENESISGRANULOMATOUS DISEASES:TB,LEPROSY,LEISHMANIA,SCHISTOSOMIASIS,SARCOIDOSIS,ACTINOMYCOSIS.

Definition:

Granulomatous inflammation is a distinctive pattern of chronic inflammatory reaction.It is a protective response to chronic infection or foreign material, preventing dissemination and restricting inflammation. Some autoimmune diseases such as rheumatoid arthritis and Crohns disease are also associated with granulomas.

Granulomas

the predominant cell type is an activated macrophage with a modified epithelial-like (epithelioid) appearance

Lymphocytes.

Occasional plasma cells.

A granuloma is a microscopic aggregation of macrophages that are transformed into epithelium-like cells surrounded by a collar of mononuclear leukocytes, principally lymphocytes and occasionally plasma cells.

Epithelioid cells fuse to form giant cells containing 20 or more nuclei.The nuclei arranged either peripherally (Langhans-type giant cell) or haphazardly (foreign body-type giant cell).These giant cells can be found either at the periphery or the center of the granuloma.

Fibrous connective tissue often surrounds granulomas (remodeling of tissue)Areas within the granuloma can undergo necrosis (prototype: caseous necrosis in tuberculosis). Necrosis can lead to calcification or liquefaction and formation of a cavern if drained.

Infectious causes:BacteriaTuberculosisLeprosyParasitesSchistosomiasis

FungiHistoplasmosisBlastomycosis

Metal/DustBerylliosisSilicosis

Foreign body Granulomas:endogenous ( keratin, necrotic bone or adipose tissue uric acid crystals)

Exogenous(wood, silica, asbestos, silicone,suture)Specific chemicals:

BerylliumSarcoidosis (unknown cause)

Type of granulomas:

Foreign body granulomas form when material such as talc, sutures, or other fibers are large enough to preclude phagocytosis by a single macrophage.

Immune granulomas - caused by insoluble particles that are capable of inducing a cell-mediated response. This type of immune response produces granulomas when the inciting agent is poorly soluble or particulate. Macrophages engulf the foreign material and process and present some of it to appropriate T lymphocytes, causing them to become activated, responding T cells produce cytokines, such as IL-2 which activates other T cells and IFN- which is important in transforming macrophages into epithelioid cells and multinucleate giant cells.

Foreign body aspiration

Berrylliosiscaseation

The classic example for the immune granuloma is that caused by the bacillus of tuberculosis. In this disease, the granuloma is referred to as a tubercle and is classically characterized by the presence of central caseous necrosis. Caseating necrosis is rare in other granulomatous diseases.There are many atypical presentations that it is always necessary to identify the specific etiologic agent by: special stains for organisms (acid-fast stains for tubercle bacilli), culture methods (tuberculosis, fungal disease), and serologic studies (syphilis). In sarcoidosis, the etiologic agent is unknown.

Granuloma: bacilli are inhaled by droplets

Bacteria are phagocytosed by alveolar macrophagesAfter amassing substances that they cannot digest, macrophages lose their motility, accumulate at the site of injury and transform themselves into nodular collections; the Granuloma

A localized inflammatory response recruits more mononuclear cells

The granuloma consists of a kernel of infected macrophages surrounded by foamy macrophages and a ring of lymphocytes and a fibrous cuff (containment phase)

Containment usually fails when the immune status of the patient changes; the granuloma caseates, ruptures and spills into the airway

Langhans Giant CellLymphocytic Rim

Pathology of Tuberculosis

2-10micrometer in length.Struntrually gram positive but also containslarge amount of lipids in the cell wall:making them acid fast.No toxinsNo sporesObligate Aerobic

Elicit granulomatous inflammation.

M. tuberculosis hominis & M. bovis M. avium, M.intracellulare in AIDS - Atypical TB

Infects one third of world population..!3 million deaths due to TB every yearUnder privileged population - Crowding, Poverty, malnutrition, economic burden.Since 1985 incidence is increasing in westAIDS, Diabetes, Immunosuppressed patients, Diabetes, Drug resistance.

Tuberculosis is a chronic communicable disease in which the lungs are the prime target,although any organ may be infected.

TUBERCULOSIS

Primary TBSecondaryTBProgressive pulmonary TBMiliary TB

PATHOGENESIS

The course of tuberculosis depends on age and immune competence AND total burden of the organismsTuberculous Infection: refers to growth of the organism in a person,whether there is symptomatic disease or not.Active Tuberculosis; refers to infection manifested by tissue destruction-----symptomatic disease.

Primary tuberculosis is the form of disease that develops in a previously unexposed and unsensitized person. Tuberculosis is a type of delayed tissue hypersensitivity to the tuberculous bacillus which elicit a cell-mediated immune response which will resists the growth and spread of the mycobacterium.This hypersensitivity reaction produces the pathologic feature of tuberculosis in immunocompetent individuals, i.e. granulomas, caseation, cavity formation.

The sequence of events which occur after inhalation of infectious agent in a previously unexposed immunocompetent individual are:The mycobacterium will gain access to the alveolar macrophage through receptors. *Once the organisms are inside the cytoplasm ofthe macrophage it will inhibit the microbicidal response of the macrophage (ineffective phagolysosome).

Multiplication of the organism inside the alveolar macrophage

processing& presentation of the antigen on the surface

A clone of sensitized T-cells proliferate, produce gamma INT. Activation of the macrophages(augmenting their capacity to kill mycobacteria)

The lytic enzymes of the activated macrophages if released, also damaged host tissues. This activation of macrophages and destruction of mycobacteria comprises the cell mediated immunity.

M. tuberculosis enters macrophages Once inside the macrophage, M. tuberculosis replicates within the phagosome by blocking fusion of the phagosome and lysosome. Thus the earliest stage of primary tuberculosis (

About 3 weeks after infection, a TH1 response against M. tuberculosis is mounted that activates macrophages to become bactericidal.TH1 cells are stimulated by mycobacterial antigens drained to the lymph node.

About 3 weeks after infection, a TH1 response against M. tuberculosis is mounted that activates macrophages to become bactericidal. TH1 cells are stimulated by mycobacterial antigens drained to the lymph node.

Mature TH1 cells, both in lymph nodes and in the lung, produce IFN-. IFN- is the critical mediator which drives macrophages to become competent to contain the M. tuberculosis infection. IFN- stimulates formation of the phagolysosome in infected macrophages, exposing the bacteria to an inhospitable acidic environment.

IFN- also stimulates expression of inducible nitric oxide synthase (iNOS), which produces nitric oxide (NO). NO helps in the destruction of several mycobacterial constituents, from cell wall to DNA.

In addition to stimulating macrophages to kill mycobacteria, the TH1 response orchestrates the formation of granulomas and caseous necrosis. Activated macrophages, stimulated by IFN-, produce TNF, which recruits monocytes. These monocytes differentiate into the "epithelioid histiocytes" that characterize the granulomatous response

In immunocompromised persons granulomas are poorly formed or not formed at all and the infection progress at the primary site in the lung ,lymph nodes or in multiple sites---------progressive primary tuberculosis.

Is characterized by:Ghon Focus ----- lung lesion of primary TB,involves upper segments of the lower lobes or lower seg.of the upper lobe.Ghon complex----- combination of a peripheral ghon focus and involved mediastinal or hilar lymphnode. Microscopically the classic lesion of TB is a caseous granuloma

Clinical and pathologic implications of primary tuberculosis1]Development of resistance to the infection.2]The foci of scarring may harbor viable bacilli for life and act as a nidus for reactivation.3]The disease may develop into progressive primary tuberculosis in immunocompro-mised patients such as AIDS patients, elderly, and malnourished children.

In patients with progressive primary tuberculosis, the tissue reaction is different.No well-formed granulomatous reaction or caseation necrosis is seen in tissue affected.Resembles acute bacterial pneumonia with lower and middle lobe consolidation, pleural effusion and hilar lymphadenopathy.Cavitary lesions are rare.Disseminated disease with tuberculous meningitis and miliary tuberculosis.

Is the pattern of disease that arises in a previously sensitized host.Is usually a reactivation of dormant primary lesions when the host resistance is lowered.Or exogenous reinfection by a high dose of virulent bacilli which occur more commonly in endemic areas.Only 5% of patients with primary disease develop secondary tuberculosis.

Pathologic features of secondary tuberculosis:In secondary pulmonary tuberculosis, the lesions involves the apices of both lungs and appear grossly as sharply circumscribed firm areas with central caseation and cavitation surrounded by fibrous wall.It can heal by fibrosis leaving a residual apical scar.Histologically, epithelioid granulomas with central caseation and Langhans type giant cells.

Other clinicopathologic forms of secondarytuberculosis depends on the organ involved andIncludesCough,low grade fever wt.loss, anorxiaCavitaton may be accompanied by haemoptysisChest radiographs show unilateral or bilateral apical cavities.

Complications of secondary TBScarring &calcificationSpread to other areasPleural fibrosis&adhesionsRupture of caseous lesionImplantation of bacteriain the larynx ---hoarseness

Miliary pulmonary diseaseOccurs when organisms drain through lymphatics into the lymphatic ducts, which empty into the venous return to the right side of the heart and thence into the pulmonary arteries. Individual lesions are either microscopic or small, visible (2-mm) foci of yellow-white consolidation scattered through the lung parenchyma.

Miliary lesions may expand and coalesce to yield almost total consolidation of large regions or even whole lobes of the lung.With progressive pulmonary tuberculosis, the pleural cavity is invariably involved, and serous pleural effusions, tuberculous empyema, or obliterative fibrous pleuritis may develop.

Miliary tuberculosis is most prominent in :the liver, bone marrow, spleen, adrenals, meninges, kidneys, fallopian tubes, and epididymis.

Isolated-organ tuberculosisMay appear in any of the organs or tissues seeded hematogenously and may be the presenting manifestation of tuberculosis

Organs that are typically involved include the meninges (tuberculous meningitis), kidneys (renal tuberculosis), adrenals (formerly an important cause of Addison disease), bones (osteomyelitis), and fallopian tubes (salpingitis). When the vertebrae are affected, the disease is referred to as Pott's disease. Paraspinal "cold" abscesses in these patients may track along the tissue planes to present as an abdominal or pelvic mass

Lymphadenitis is the most frequent form of extrapulmonary tuberculosis, usually occurring in the cervical region ("scrofula"). Intestinal tuberculosis contracted by the drinking of contaminated milk. In developed countries today, intestinal tuberculosis is more often a complication of protracted advanced secondary tuberculosis, secondary to the swallowing of coughed-up infective material.

Adrenal TB - Addison Disease

Spinal TB - Potts Disease

Diagnosis of TB

Clinical features are not confirmatory.Zeil Nielson Stain - 1x104/ml, 60% sensitivityRelease of acid-fast bacilli from cavities intermittent.3 negative smears to assure low infectivity*Culture most sensitive and specific test.Conventional Lowenstein Jensen media 3-6 wks.Automated techniques within 9-16 daysPCR is available, but should only be performed by experienced laboratoriesPPD for clinical activity / exposure sometime in life.

AFB - Ziehl-Nielson stain

Colony Morphology LJ Slant

BacterialTuberculosis (Mycobacterium tuberculosis)Leprosy (Mycobacterium leprae)Syphilitic gumma (Treponema pallidum)ParasiticSchistosomiasis (Schistosoma mansoni, S. haematobium,S. japonicum)FungalHistoplasma capsulatumBlastomycosisCryptococcus neoformansCoccidiodes immitisInorganic Metals or DustsSilicosisBerylliosisForeign BodySuture, breast prosthesis, vascular graftUnknownSarcoidosis

Gram stainMost bacteriaAcid fast stainMycobacteria, nocardiae (modified)Silver stainsFungi, legionellae, pneymocytosisPeriod acid-SchiffFungi, amebaeMucicarmineCryptococciGiemsaCampylobacteria, leishmaniae, malaria, parasitesAntibody probesViruses, rickettsiaeCultureAll classesDNA probesViruses, bacteria, protozoa

PolarizingmicroscopeForeign body

Tuberculin TestIt is a classic example of delayed hypersensitivity.The tuberculin reaction, is produced by the intracutaneous injection of tuberculin, a protein-lipopolysaccharide component of the tubercle bacillus.

In a previously sensitized individual, reddening and induration of the site appear in 8 to 12 hours, reach a peak in 24 to 72 hours, and thereafter slowly subside. Morphologically, delayed type hypersensitivity is characterized by the accumulation of mononuclear cells around small veins and venules, producing a perivascular "cuffing" .

Plasma proteins escape, giving rise to dermal edema and deposition of fibrin in the interstitium.The latter appears to be the main cause of induration, which is characteristic of delayed hypersensitivity skin lesions.In fully developed lesions, the lymphocyte-cuffed venules show marked endothelial hypertrophy and, in some cases, hyperplasia.

Leprosy/Hansen disease

PathogenesisM. leprae is an acid-fast obligate intracellular organism that grows very poorly in culture. It grows more slowly than other mycobacteria and grows best at 32 to 34C, the temperature of the human skin

Is a slowly progressive infection caused by Mycobacterium leprae, affecting the skin and peripheral nerves and resulting in disabling deformities. M. leprae is likely to be transmitted from person to person through aerosols from lesions in the upper respiratory tract.

Inhaled M. leprae, like M. tuberculosis, is taken up by alveolar macrophages and disseminates through the blood, but grows only in tissues of the skin and extremities. leprosy remains endemic among an estimated 10 to 15 million people living in poor tropical countries

Like M. tuberculosis, M. leprae secretes no toxins, and its virulence is based on properties of its cell wall. The cell wall is similar enough to that of M. tuberculosis. Cell-mediated immunity is reflected by delayed type hypersensitivity reactions to dermal injections of a bacterial extract called lepromin

Leprosy has two strikingly different patterns of disease. Patients with the less severe form, tuberculoid leprosy, have dry, scaly skin lesions that lack sensation. They often have large, asymmetric peripheral nerve involvement.

The more severe form of leprosy, lepromatous leprosy, includes symmetric skin thickening and nodules. This is also called anergic leprosy, because of the unresponsiveness (anergy) of the host immune system.

In lepromatous leprosy, damage to the nervous system comes from widespread invasion of the mycobacteria into Schwann cells and into endoneural and perineural macrophages. - In advanced cases of lepromatous leprosy, M. leprae is present in sputum and blood.

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

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

Morphology of Tuberculoid leprosyNeuronal involvement dominates tuberculoid leprosy. Nerves become enclosed within granulomatous inflammatory reactions. Nerve degeneration causes skin anesthesias and skin and muscle atrophy that render the patient liable to trauma of the affected parts, with the development of indolent skin ulcers.

Tuberculoid leprosyContractures, paralyses, and autoamputation of fingers or toes may ensue. Facial nerve involvement can lead to paralysis of the eyelids, with keratitis and corneal ulcerations.

On microscopic examination, all sites of involvement disclose granulomatous lesions closely resembling those found in tuberculosis, and bacilli are almost never found. The presence of granulomas and absence of bacteria reflect strong T-cell immunity.

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Granulomatous Inflammation