4. Chronic Inflammation 27 Aprit2021— 17.27 Inflammation of prolonged duration (weeks or months} in which inflammation, tissue damage, and healing occurs at the same time, in varying combinations. Chronic inflammation may: 1. Follow an acute inflammation, which does not resolve (ex: chronic osteomyelitis} or 2. Begin as insidious, low grade, chronic, response w/o any acute inflammatory reaction, Sequelae: chronic inflammation can cause disabling tissue damage. Ex: rheumatoid arthritis, TB and atherosclerosis CAUSES: 1. Persistent infections: microbes that are difficult to eradicate elicit delayed type of hypersensitivity—produce chronic inflammation ex: mycobacteria,and certain viruses, fungi and parasites. Some agents may cause a distinct pattern of chronic inflammation—granulomatous reaction 2. Immune-mediated inflammatory (hypersensitivity) diseases: + Autoimmune di rheumatoid arthritis + Allergic reactions: bronchial asthma + Unregulated immune response: inflammatory bowel disease 3. Prolonged exposure to toxic injurious agents: + Exogeneous: silica—non biodegradable inanimate exogenous material. Person exposed to silica particles for long time—inflammatory lung disease—silicosis + Endogenous: atherosclerosis—disease of arterial intima—represents a chronic inflammatory process partly due to endogenous toxic plasma lipid components Most common cause of chronic inflammation—persistent infection MORPHOLOGIC FEATURES: Mononuclear cells infiltrate: macrophages, lymphocytes, and plasma cells + Tissue destruction: by the persistence of causative agent or by the inflammatory cells + Healing by fibrosis CHRONIC INFLAMMATORY CELLS AND MEDIATOR‘ Macrophages : Predominant cell ‘Tissue macrophage: Derived from hematopoietic stem cells in the bone marrow and from progenitors in the embryonic yolk: sac and fetal liver during early development MACROPHAGE EVENTS IN INFLAMMATION: * Monocytes also emigrate into extravascular tissues early in acute inflammation— predominant cell type within 48 hrs * On reaching extravascular tissue—monocyte transformed into tissue macrophage Macrophage activation: By 2 major pathways© Classical macrophage activation: -Mediators of activation: brought out mainly by: + Microbial products:ex: endotoxin + Tcell derived signals: mainly cytokines (for ex: IFN-y) + Foreign substances: ex: crystals and particulate matter products of activated macrophages: + Lysosornal enzymes + Nitric oxide + Reactive oxygen species (ROS) function: phagocytosis and killing/ elimination of ingested microbes © Alternate macrophage activation: -mediators of activation: cytokines IL-4 and IL-13 produced by T cells and other cells -function: initiation of the tissue repair (they are not bactericidal] Functions of macrophages in inflammation: ‘© Phagocytosis: ingestion and elimination of microbes and necrotic tissue © Initiation of tissue repair © Secretion of mediators of inflammation: cytokines (TNF, IL-1, chemokines, etc] and arachidonic acid metabolites © Display signal to T-cells and respond signals form T-cells : responsible for the feedback loop for defense against many microbes by cell- mediated immune response hocyt ‘© Band T lymphocyte: found in both antibody- mediated and cell mediated immune reactions © B lymphocytes: may develop into plasma cells and produce antibodies either against foreign or self-antigens in the inflammatory site © T lymphocytes: important being CD4+ helper T cells which has 3 subtypes namely: -TH1: Produce INF-y and activates macrophage in the classical pathway. ~TH2: Produce IL-4, IL-5 and IL-13 which recruit and activate eosinophils and activate macrophages through alternate pathway. Involved in defense against helminthic infestation and allergic reaction. -THI7: Produce IL-17 and other cytokines which recruit neutrophils and monocytes. Other cells: ‘© Plasma cells: derived from activated B lymphocytes and produce antibodies either against foreign or self-antigens © Eosinophils: seen in immune reactions mediated by IgE and in parasitic infections. Chemokine which attracts eosinophil recruitment- eotaxin. Eosinophil granules contain major basic protein—toxic to parasites and also destroy the epithelial cells © Mast cells: distributed in CTs and participate in both acute and chronic inflammatory reactions. Seen in allergic reactions to foods, insect venom or drugs. TYPES OF CHRONIC INFLAMMATIO! 1. Chronic non-specific inflammation 2. Granulomatous inflammation Eosinophils seen in’ + Hypersensitivity reactions+ Parasitic infestations GRANULOMATOUS INFLAMMATION: Granuloma—distinctive type of chronic inflammation characterized by microscopic aggregation of activated macrophages (that are transformed into epithelium like/ epithelioid cells] with scattered lymphocytes + Older granulomas—rim of fibroblasts and CT as the outermost layer + Structurally, granuloma consists of + Epithelioid cells: modified macrophages which resemble epithelial cells -Pale pink granular cytoplasm—indistinct cell borders—appearing to merge into one another -Nucleus—oval or elongate—may show folding of the nuclear membrane—less dense nucleus than lymphocyte + Giant cells: epithelioid cells fuse to form giant cells—found in the periphery or sometimes in the center of the granulomas -May attain diameters of 40-50 pm and have many small nuclei -Nuclei—20 or more—may be arranged either peripherally (Langhans-type giant cell] or haphazardly (foreign body-type giant cell] + Lymphocytes: cell mediated immune reaction to antigen, lymphocytes form an integral part of granulomatous inflammation + Necrosis: sometimes granulomas are associated with central necrosis (ex: TB) ~Granulomas in Crohn disease, sarcoidosis, and foreign body reactions does not have necrotic centers—non caseating granulomas + Fibrosis: granulomas may heal by producing extensive fibrosis ‘TYPES OF GRANULOMAS: Depending on the pathogenesis—2 types: Foreign body granulom: + Develops against relatively inert foreign bodies which do not incite any specific inflammatory ot immune response (absence of T-cell mediated immune responses) + Foreign body which elicit granuloma—suture materials, talc (associated with iv drug abuse}, or other fibers that are large enough to be phagocytosis by a macrophage + Foreign material—in the center of the granuloma—if seen with polarized light Immune granuloma: + Caused by agents /microbes capable of inducing a persistent T-cell-mediated immune response + Develop when the inciting agent is difficult to eradicate, such as a persistent microbe (ex: Mycobacterium tuberculosis) or a self- antigen + Macrophages activate T cells to produce cytokines, such as IL-2—in turn activates other T cells, perpetuating the response, and IFN-y, which activates the macrophages + Granuloma in TB—tubercle - central caseous necrosis (due to a combination of hypoxia and free radical mediated injury} + Additional tests / investigations to identify the etiologic agent ~ Special stains, e.g, acid-fast stains for tubercle bacilli — Culture methods, e.g. in tuberculosis and fungal diseases ~ Molecular techniques (e.g. the polymerase chain reaction in tuberculosis) ~ Serologic studies [e.g, in syphilis) Examples of granulomatous inflammation:ee ; BOK 4.1:Types of giant cells Fg. 42: Varousypesct gars GRANULOMATOUS DISEASES: + Mycobacterium -- slender aerobic rods—straight or branching chains—have a waxy cell wall composed of mycolic acid—responsible for their acid fast nature— weakly gram +ve + Acid fast—mycobacteria retain stain even on treatment with a mixture of acid and alcohol LEPROSY: + Hansen disease + Chronic, granulomatous, slowly progressive, destructive infection caused by Mycobacterium leprae + Sites of involvement—peripheral nerves, skin and mucous membranes (nasal) and results in disabling deformities Mycobacterium Leprae: + Slender, weakly acid fast intracellular bacillusResembles Mycobacterium tuberculosis but is less acid fast Froliferates at low temperature of the human skin Cannot be cultured on artificial media or in cell culture Lepra bacilli grow at sites where temperature is below that of the internal organs Ex: foot pads of mice, ear lobes of hamsters, rats and other rodents Antigen in lepra bacilli: cell wall—2 antigens—M. Leprae specific phenolic glycolipid (PGL-1] and lipoarabinomannan [LAM] + Mode of transmission: low communicability + M, leprae: Grows best in cooler tissues: (1] Skin, (2) Peripheral nerves, (3) Anterior chamber of eye, (4) Upper respiratory tract and (5) Testis. 1. Inoculation /inhalation: person to person through aerosols form asymptomatic lesions in the upper respiratory tract + Inhaled M. leprae—taken up by alveolar macrophages and disseminates through the blood—replicates only in relatively cool tissues of the skin and extremities 2. Intimate contact: many years with untreated leprosy patients—shed many bacilli from damaged skin, nasal secretions, mucous membrane of mouth and hair follicles Source of infection: nasal secretions or ulcerated lesions of patients Only bacterium that invades peripheral nerves, Incubation period—5-7 years CLASSIFICATIO ‘A. Ridley and Jopling classification: Depends on the clinicopathological spectrum of the disease—determined by the immune resistance of the host 5 groups—2 extremes or polar forms—tuberculoid and lepromatous aseyctngclsstcaon Secor astcaton of eposy f T + 1 ihe and oping satiation a Es ee tprenr tt) | fptmiotet) (68) Wren Fig 43:8 sets Tuberculoid leprosy (TT): polar form that has maximal immune response. Borderline tuberculoid (BT): immune response b/w BB and TT Borderline leprosy [BB]: exactly b/w the two polar forms of leprosy Borderline lepromatous (BL): immune response b/w BB and LL Lepromatous leprosyiLL}: least immune response Variants of leprosy: + Indeterminate leprosy: initial non specific type of leprosy + Pure neural leprosy—neurologic involvement is the main feature + Histoid leprosy: variant of lepromatous leprosy—skin lesions grossly resemble nodules of dermatofibroma and microscopically shows numerous lepra bacilli ohewe B. WHO classification Paucibacillary and muttibacillary + Paucibacillary—all cases of tuberculoid leprosy and some cases of borderline type + Multibacillary—all cases of lepromatous leprosy and some cases of borderline type PATHOGENESIS: ‘Mycobacterium leprae- does not secrete any toxins—virulence depends on properties of its cell wall (similar to M. tuberculosis + Immunization with BCG may provide some protection against M. leprae infection + Tuberculoid leprosy—strong TH1 response compared to weak TH1 response inlepromatous leprosy + Cell mediated immunity—reflected by delayed-type hypersensitivity reactions to dermal injections of a bacterial extract called lepromin + T-helper (TH1] lymphocyte response to M. leprae, determines whether an individual develop tuberculoid or lepromatous type of leprosy. -Tuberculoid leprosy patients—TH1 response—secretes IL-2 and IFN-y. IFN-y is essential for an effective host macrophage response -Lepromatous leprosy—weak TH1 response and, in some a relative increase in the TH2 response --results in a poor cell-mediated immunity --proliferation of lepra bacilli Sometimes antibodies produced against M. leprae antigens, but usually not protective. ‘These can form immune complexes with free antigens and lead to erythema nodosum, vasculitis, and glomerulonephritis Morphology: ‘Two extremes or polar forms ~ tuberculoid and lepromatous 1. Tuberculoid leprosy: less severe form—very slow course—most patients die -Lesion in skin’ «Number of lesions—single or very few = Site—face, extremities or trunk « Type—tocalized, well demarcated, red or hypopigmented, dry , elevated, skin patches having raised outer edges and depressed pale centers (central healing] As they progress they develop irregular shapes with induration -Nerve involvement: = Dominating feature in tuberculoid leprosy « Nerves surrounded by granulomatous inflammatory reactions and may destroy small (ex: peripheral twigs) nerves «Nerve involvernent—toss of sensation in skin—atrophy of skin and muscle. Affected parts—liable to trauma, and lead to the development of chronic skin ulcers « Consequences: contractures, paralyses, and autoamputation of fingers or toes Involvement of facial nerve can lead to paralysis of fingers or toes. Involvement of facial nerve can lead to paralysis of the eyelids, with keratitis and corneal ulcerations -Microscopy: «= Granuloma: well formed, circumscribed and non- caseating. In all involved sites and in the dermis of skin, tuberculoid leprosy because the granulomas resemble those found in TB. Composed of epithelioid cells [modified macrophages), Langhans giant cells and lymphocytes. = Absence of Grenz zone: granulomas in the dermis extend to the basal layer of the epidermis [w/o a clear/ Grenz zone] « Fite-Faraco (modified Z-N stain for demonstration of lepra bacillus} stain generally does not show lepra bacillus, hence the name “paucibacillary” leprosy. « Perineural (surrounding nerve fibers} inflammation: By lymphocytes « Strong T-cell immunity: It is responsible for granulomas formation, without lepra bacilli, Tuberculoid leprosy: 1. Good immune response 2. Lepromin test positive 3. Noncaseating granuloma in the skin 4. Nerve involvement. 2. Lepromatous leprosy: more severe form — anergic leprosy—because of theunresponsiveness of the host immune system. Sites involved: -Lesion in skin: = Thickening of skin and multiple, symmetric, macular, papular, or nodular lesions, Nodular skin lesions may ulcerate. Most skin lesions—hypoesthetic or anesthetic + More severe involvement of the cooler areas of skin (ex: earlobes, wrists, elbows, and knees, and feet], than warmer areas (ex: axilla and groin) « With progression, the nodular lesions in the face and earlobes may coalesce to produce a lion like appearance known as leonine facies. This may be accompanied by loss of eyebrows and eyelashes. -peripheral nerves: = Ulnar and peroneal nerves—symmetrically invaded with mycobacteria + Loss of sensation and trophic changes in the hands and feet may follow the damage to the nerves ~Testes: severely involved—destruction of the seminiferous tubules—sterility -Other sites: = Anterior chamber of the eye—blindness = Upper airways—chronic nasal discharge and voice change -Microscopy of skin lesion: = Flattened epidermis—epidermis is thinned and flattened (loss of rete ridges) over the nodules = Grenz (clear] zone: a characteristic narrow, uninvolved dermis (normal collagen|-- separates the epidermis from nodular accumulations of macrophages + Lepra cells: nodular lesions contain large aggregates of lipid-laden foamy macrophages (lepra cells, Virchow cells), filled with aggregates (globi) of acid fast lepra bacilli (M.leprae) + Fite-Faraco (acid fast | stain—shows numerous leprabacilli (“red snappers” within the foamy macrophages. They may be arranged in a parallel fashion like cigarettes in a pack, + Due to the presence of numerous bacteria, lepromatous leprosy—muttibacillary In advanced cases, M. leprae—in sputum and blood Individuals with intermediate forms of disease—borderline leprosy 3. Borderline leprosy: + Borderline tuberculoid(BT): shows epithelioid cells and numerous lymphocytes with a narrow clear subepidermal zone. Lepra bacilli—few—in nerves + Borderline lepromatous (BL): shows predominantly histiocytes, few epithelioid cells and lymphocytes. Numerous lepra bacilli + Mid-borderline (BB) dimorphic form—sheets of epithelioid cells w/o any giant cells, Few lymphocytes in the perineum. Lepra bacilli_mostly in nerves 4. Indeterminate leprosy: non-specific and few findings help in suspecting leprosy. Include: i, Local infiltration of lymphocytes or mononuclear cells surrounding the skin adnexa (ex: hair follicles and sweat glands] or around blood vessels ii, Involvement of nerve involvement (if seen strongly favors the diagnosis) and ili, Finding of lepra bacilli (which confirms the diagnosis] LEPROMIN TEST:Not a diagnosis test for leprosy. Used for classifying leprosy based on the immune response Procedure: an antigen extract of M.leprae called leprornin is intradermally injected. Mitsuda reaction’ Reaction: + Early positive reaction—as an indurated area in 24-48 hrs - Fernandez reaction + A delayed granulomatous reaction appearing after 3-4 weeks—Mitsuda reaction Interpretation: + Lepromatous leprosy—shows negative lepromin test due to suppression of cell mediated immunity + Tuberculoid leprosy—shoes positive lepromin test because of delayed hypersensitivity reaction. Lepromatous leprosy: 1. Leonine facies 2. Low resistance 3. Thinned epidermis 4. Grenz zone 5. Lepra cells filled with acid-fast bacilli 6. Lepromin test negative. Uses of lepromin test 1. Classification of leprosy 2. Evaluation of cell-mediated immunity status in patient 3. Know the prognosis Reactions in leprosy: Immunity in leprosy may change spontaneously or following treatment + Type I reaction: -borderline leprosy—most unstable form of leprosy where immune status may shift up or down. 2 types: @ Upgrading reactions: If immunity improves, the disease may shift towards tuberculoid leprosy. ‘ Downgrading reaction: If the immunity decreases, the disease moves towards lepromatous leprosy + Type II reaction or erythema nodosum leprosum: -mostly in lepromatous leprosy—when on treatment -clinical features: (1] Tender red plaque or nodules and (2) fever, malaise and arthralgia -Microscopy: @ Necrotizing vasculitis © Lepra bacilli in the foamy macrophagesomatos nd ier ea. Symmetical, multiple idefined, macular, Asymmetrical, hypopigmented, wel fined macular nodular Leonine facies, los of eyebrows, Minimal disfigurement pendulous earlobes, clawhands saddle Nerve involvement Seen, but with less severe sensory loss Common with sensory disturbances than tuberculid Microscopy of skin lesions Type oflesion Nodular or difuse collections of Lepra__Noncaseating granulomas composed of. ‘els wthin dermis epithelioid cells and giant cells ‘Grenz/clearzone between inflammatory Present ‘Absent ‘ells and epidermis Lepra bac Plenty within thelepraclisas globular Rareifany masses (glob) Bacilary index 4ors ° ‘Other features Immunity Suppeessed low resistance Good immunityhigh resistance Lepromin test Negative Postive Diagnosis of Leprosy ‘Morphological index (i): + Staining of smears or skin biopsy + Measure of number of acid fst bacil (AFB) n skin scrapings = ‘eid fast Ziehl Neeser stain ‘that stan uniformly bright. = Fte-Faraco stain + Contelates with viablty of AFB. + Molecular method—PCR Bacteriological index (8): Quantifis M leprae in tissue or smears It scored from 1+ to 6+ ange from 1 to 10 baci per 100 fils to > 1000 pe fed) as mutbacilay leprosy whereas Blof +s termed paucbacilary. DIAGNOSIS OF LEPROSY: 1. Clinical examination: + Sensory testing: + Examination of peripheral nerve 2. Demonstration of acid fast bacilli: + Skin smears prepared by slit and scrape method + Mycobacterium leprae—demonstrated in tissue sections, in split skin smears by splitting the skin and in nasal smears by the following techniques -Acid fast [Z-N]) staining -Fite-Faraco staining procedure—modification of ZN procedure and is considered vetter for more adequate staining of tissue sections -Gomori methenamine silver (GMS} staining can also be employed + Nasal swabs stained by ZN method: Staining procedure similar to M. tuberculosis but can be decolorized by lower concentration (5%| of sulfuric acid (less acid-fast) 3. Skin biopsy: Fite-Faraco staining procedure is a modified ZN procedure and is better for tissue sections. 4. Nerve biopsy 5, Molecular method: Polymerase chain reaction (PCR) SYPHILIS: + IgM antibodies to PGL-1 antigen: Found in 95% of patients of lepromatous leprosy and in 60% of tuberculoid leprosy + Caused by spirochete Treponema pallidum + Spirochetes—gram ve, slender corkscrew shaped bacteria covered in amembrane called outer sheath—may mask its antigens from the host immune response + Syphilis (Ilues|-- chronic, STD caused by Treponema pallidum. ETIOLOGY: Treponema pallidum + Thin, delicate, corkscrew shaped spirochete—10um long with tapering ends—10 regular spirals Actively motile—rotation round the long axis, backward and forward motion Can't be grown in artificial media Doesn't stain with ordinary bacterial stains—too slender to be seen in gram stain Visualized by silver stains, dark field examination and immunofluorescence techniques. + Source of infection: open lesion of primary or secondary syphilis. Lesions in the mucous membranes or skin of the genital organs, rectum, mouth, fingers, or nipples. + Mode of transmission: -sexual contact -Transplacental transmission—congenital syphilis -Blood transfusion -Direct contact: with the open lesion—rare BASIC MICROSCOPIC LESION: Consists of + Mononuclear inflammatory infiltrate: predominantly of plasma cells and lymphocytes + Obliterative endarteritis: characteristic obstructive vascular lesion in which mononuclear infiltrates surround small arteries and arterioles (periarteritis) STAGES OF SYPHILIS: + Treponema pallidum—passes from the site of inoculation to regional lymph nodes and enters to the systemic circulation and disseminate throughout the body + Can be congenital or acquired + Course of acquired syphilis - 3 stages: i, Primary syphilis ii, Secondary syphilis ili, Tertiary syphilis seine come a sai =..| See |e ro Soo lac Seiagsme | jeter Panioss iymehadenopaty moore — Peteceis 3 Eighth-nerve deainess, ig Ate Vasious PRIMARY SYPHILIS. Develops about 3 weeks after contact with an infected individual and the lesion is primary chancre.Primary Chancre: Classical lesion of primary syphilis + Sites: penis or scrotum in men and cervix, vulva and vaginal wall in women. May also be seen in the anus or mouth + Gross features: single, firm , nontender (painless), slightly raised , red papule (chancre] up to several centimeters in diameter. Erodes to create a clean based shallow ulcer. Because of the induration surrounding the ulcer, it is designated as hard chancre + Demonstration of treponema: plenty of treponemes demonstrated in chancre by i. Silver stains (ex: Warthin-Starry stain] or ii, Immunofluorescence techniques or ili, Dark field examination + Microscopy: -Mononuclear infiltration: consisting of plasma cells, with scattered macrophages and lymphocytes—also seen surrounding the blood vessels [periarteritsis} Blood vessels with endarteritis: endothelial cell proliferation which progresses to intimal fibrosis. Primary syphilis: Chancre is the painless lesion seen in the external genitalia with regional lymphadenitis. Regional Lymphadenitis It is due to nonspecific acute or chronic inflammation. + Treponemes may spread throughout the body by blood and lymphatics even before the appearance of the chancre. + Symptoms: Usually, painless and often unnoticed + Fate: It heals in 3-6 weeks with or without therapy. Secondary Syphilis Secondary syphilis: 1. Mucocutaneous lesions 2. Generalized lymphadenopathy SECONDARY SYPHILIS: Secondary syphilis 1, Mucocutaneous lesions 2. Generalized lymphadenopathy Develops 2-10 weeks after the primary chancre in approx 75% untreated patients. Manifestations: due to systemic spread and proliferation of the spirochetes within the skin and mucocutaneous tissues. MUCOCUTANEOUS LESIONS: Painless, superficial lesions—contain spirochetes—infectious Skin lesion + Skin rashes: consist of discrete red-brown macules less than 5 mm in diameter— may be scaly / pustular/ annular—more frequent on the palms of the hands, or soles of the feet + Condylomata lata: broad based, elevated plaques with numerous spirochetes— seen in moist areas of the skin, such as the anogenital region perineum, vulva, and scrotum], inner thighs, and axillae. Mucosal lesion: Oral cavity or vagina as silvery-gray superficial erosions—contain numerous T pallidum-- highly infectious. Microscopy: similar to primary chancre, Le. infiltration by plasma cells and endarteritis obliterans. Painless lymphadenopathy: Involves epitrochlear nodes and shows plenty of spirochetes Symptoms: Mild fever, malaise, and weight loss—common in secondary syphilis—may last for several weeks. Lesions subside even w/o treatment. ‘Treponema pallidurn—identified in lesions of primary or secondary syphilisTERTIARY SYPHILI Involves mainly CVS, CNS and focal lesions called gumma. + After the lesions of secondary syphilis have subsided patients enters an asymptomatic latent phase of the disease + Latent period—s yrs or more even decades), but spirochetes continue to multiply—rare if patient gets adequate treatment, but can occur in about one- third of untreated patients + Focal ischemic necrosis due to obliterative endarteritis is responsible for many of the processes associated with tertiary syphilis Manifestations: three main manifestations—cardiovascular syphilis, neurosyphilis, and so-called benign tertiary syphilis—may occur alone or in combination. CARDIOVASCULAR SYPHILIS: Most frequently invoives the aorta—syphilic aortitis + Syphilitic aortitis: more than 80% of cases of tertiary disease, and affects the proximal aorta + Saccular aneurysm and aortic valve insufficiency: -Occlusion of the vasa vasorum due to endarteritis leads to necrosis and scarring of the aortic media, causing a loss of elasticity, strength and resilience. ~ Gradual weakening and slow progressive dilation of the aortic root and arch, causes aortic valve insufficiency and aneurysms of the proximal aorta. Syphilitic aneurysms are saccular and seen in the ascending aorta, which is unusual site for the more common atherosclerotic aneurysms ~ On gross examination, the aortic intima appears rough and pitted (tree-bark appearance} + Myocardial ischemia: Narrowing of the coronary artery ostia (at the origin from aorta] caused by subintimal scarring may lead to myocardial ischemia/ infarction. Cardiovascular syphilis: Involves proximal aorta and lead to saccular aneurysm of aorta and aortic valve incompetence. Syphilis never causes aortic stenosis NEUROSYPHILIS: asymptomatic or symptomatic Asymptomatic neurosyphilis: detected by CSF examination—shows pleocytosis, increased numbers of inflammatory cells), elevated protein levels, or decreased glucose. Antibodies also detected in CSF—most specific test for neurosyphilis Symptomatic disease: takes one of the several forms Chronic meningovascular disease: chronic meningitis—involves base of brain, cerebral convexities and spinal leptomeninges + Tabes dorsalis: demyelination of posterior column, dorsal root and dorsal root ganglia. + General paresis of insane: generalized brain parenchymal disease with dementia—general paralysis of insane BENIGN TERTIARY SYPHILIS + Formation of nodular lesions called gummas in any organ or tissue + Gammas reflect development of delayed hypersensitivity to the spirochete + Gummas—very rare—found in patients with AIDS SYPHILITIC GUMMAS: Central area of coagulative necrosis surrounded by plump, palisading macrophages, fibroblasts and plenty of plasma cells Gumma May be single or multiple + White-gray and rubbery + Vary in size from microscopic lesions to large tumor-like masses+ In most organs but mainly involve: -Skin, subcutaneous tissue and the mucous membranes of the upper airway and mouth, ~Bone and joints: It causes local pain, tenderness, swelling, and sometimes pathologic fractures ~ In the liver, scarring due to gummas may cause a distinctive hepatic lesion known as hepar lobatum. + Microscopy: Center of the gummas show coagulative necrosis -surrounded by plump, palisading macrophages, fibroblasts and plenty of plasma cells ‘Treponemes are scant in gummas CONGENITAL SYPHILIS: TRANSPLACENTAL TRANSMISSIOI + T.Pallidum can cross placenta and spread from infected mother to the fetus [during pregnancy), + Transmission occurs, when mother is suffering from primary or secondary syphilis (when the spirochetes are abundant, Because of routine serologic testing for syphilis in done in all pregnancies) congenital syphilis is rare Manifestations: divided into: 1. Intrauterine death and perinatal death 2. Early (infantile ) syphilis: first 2 yrs of life—nasal discharge and congestion (snuffles} + A desquamating or bullous eruption/rash—- epidermal sloughing of the skin, mainly in the hands and feet, around mouth and anus + Skeletal abnormalities -Syphilitic osteochondritis: Inflammation of bone and cartilage is more distinctive inthe nose. Destruction of the vomer causes collapse of the nasal bridge—saddle nose deformity -Syphilitic periostitis: involves the tibia—causes excessive new bone formation on the anterior surfaces and leads to anterior bowing or saber shin + Liver: diffuse fibrosis in the liver—hepar lobaturn + Lungs: diffuse interstitial fibrosis—lungs appear pale and airless (pneumonia alba] 3. Late (tardive) syphilis: manifests 2 yrs after birth. About 50% of untreated children with neonatal syphilis will develop late manifestations + Manifestations: distinctive manifestation is Hutchinson's triad. Interstitial keratitis -Hutchinson's teeth: like small screw-drivers or peg-shaped incisors, with notches in the enamel -Eighth-nerve deafness LABORATORY DIAGNOSIS: Immunofluorescence of exudate from the chancre—impt for diagnosis in primary syphilis + Microscopy and PCR useful + Serological tests -Nontreponemal antibody tests: measure antibody to cardiolipin, a phospholipid present in both host tissues and T. pallidum, + These antibodies—detected by the rapid plasma reagin and Venereal disease research laboratory (VDRL] tests + False positive VDRL test: found in certain acute infections, collagen vascular diseases (ex: systemic lupus erythematosus], drug addiction, pregnancy, hypergammagiobulinemia of any cause, and lepromatous leprosy. + Antitreponemal antibody tests: measure antibodies which react with T.pallidum. Include -Fluorescent treponemal antibody absorption test [FTA] - Microhemagglutination assay for T. pallidum antibodies.