MYCOBACTERIA : slender, aerobic rods that grow in straight or branching chains. cell wall composed of mycolic acid , which makes them acid fast (retain stains even on treatment with a mixture of acid and alcohol). Mycobacteria stain weakly positive with Gram stain.Tuberculosis: M. tuberculosis responsible for most cases of tuberculosis. Reservoir of infection is humans with active tuberculosis. Most infections are acquired by person-to-person transmission of airborne droplets of organisms.
Pathogenesis: M. tuberculosis enters macrophages by endocytosis mediated by several macrophage receptors. Once inside macrophage, M. tuberculosis replicates within phagosome by blocking fusion of phagosome and lysosome. Thus the earliest stage of primary tuberculosis (<3 weeks) in nonsensitized individual is characterized by proliferation of bacteria in pulmonary alveolar macrophages and airspaces, with resulting bacteremia . Despite bacteremia, most patients at this stage are asymptomatic or have a mild flulike illness.
About 3 weeks after infection, Mature TH1 cells produce IFN-γ ( Interferon-γ ) which drives macrophages to contain infection. IFN-γ stimulates formation of phagolysosome in infected macrophages. IFN-γ also stimulates expression of inducible nitric oxide synthase (iNOS), which produces nitric oxide (NO) and other free radicals capable of oxidative destruction of several mycobacterial constituents, from cell wall to DNA. Activated macrophages also produce TNF, which recruits monocytes which differentiated into "epithelioid histiocytes" that characterize the granulomatous response.
Morphology :Primary Tuberculosis: inhaled bacilli implant in lower part of upper lobe or upper part of lower lobe. As sensitization develops, a 1- to 1.5-cm area of gray-white inflammatory consolidation known as Ghon focus. In most cases, center of this focus undergoes caseous necrosis. Tubercle bacilli drain to regional nodes, which also caseate. This combination of parenchymal lung lesion and regional nodal involvement is referred to as Ghon complex .
In 95% of cases, cell-mediated immunity controls the infection. Hence, Ghon complex undergoes progressive fibrosis, often followed by radiologically detectable calcification (Ranke complex). Histologically: characteristic granulomatous inflammatory reaction forms both caseating and non-caseating tubercles( granuloma). Individual tubercles are microscopic; when multiple granulomas coalesce they become macroscopically visible.
• The granulomas are usually enclosed within a fibroblastic rim punctuated by lymphocytes.• Multinucleate giant cells ( langhans giant cells) are present in granulomas.• Immunocompromised people do not form granulomas• No cavity formation in primary T.B.
Secondary Tuberculosis: The initial lesion is usually a small apical focus of consolidation, less than 2 cm in diameter. Such foci are sharply circumscribed, firm, gray-white to yellow areas that have a variable amount of central caseation and peripheral fibrosis . In favorable cases, the initial parenchymal focus undergoes progressive fibrous encapsulation, leaving only fibrocalcific scars. Histologically, the active lesions show characteristic coalescent tubercles with central caseation.
The apical lesion enlarges with expansion of area of caseation. Erosion into a bronchus evacuates the caseous center, creating a ragged irregular cavity lined by caseous material that is poorly walled off by fibrous tissue. With adequate treatment, the process may be arrested. Irregular cavities, now free of caseous necrosis, may remain or collapse in surrounding fibrosis. If treatment is inadequate or if host defenses are impaired, the infection may spread by direct expansion via dissemination through airways, lymphatic channels, or vascular system.
Diagnosis: History and physical and radiographic findings of consolidation or cavitation in apices of lungs. Acid-fast smears and cultures of sputum. PCR amplification of M. tuberculosis DNA.
Miliary pulmonary disease :• occurs when organisms drain through lymphatics into lymphatic ducts, which empty into venous return to right side of heart and hence into pulmonary arteries.• Individual lesions are either microscopic ,or small visible (2 mm) foci of yellow-white consolidation scattered throughout lung parenchyma .• With progressive pulmonary tuberculosis, the pleural cavity is invariably involved, and tuberculous empyema may develop.
Systemic miliary tuberculosis : ensues when infective foci in lungs seed pulmonary venous return to heart. the organisms subsequently disseminate through systemic arterial system. Almost every organ in body can be seeded. Organs that are typically involved include meninges (tuberculous meningitis), kidneys (renal tuberculosis), adrenals (Addison disease), bones (osteomyelitis), and fallopian tubes (salpingitis), vertebrae (Potts disease),and Paraspinal "cold" abscesses.
NOTES: Lymphadenitis is most frequent form of extra-pulmonary tuberculosis, usually occurring in cervical region ("scrofula ). Oropharyngeal and intestinal tuberculosis by drinking milk contaminated with M. bovis is rare in developed nations, but it is still seen in countries that have unpasteurized milk. In developed countries today, intestinal tuberculosis is more often a complication of advanced secondary tuberculosis secondary to swallowing of coughed-up infective material.
Mycobacterium Avium-Intracellulare Complex(MAC):• is common in soil, water, dust, and domestic animals.• infection is uncommon, except among people with AIDS and low levels of CD4+ lymphocytes (<60 cells/mm3).• MAC causes widely disseminated infections in many organs, commonly lungs and gastrointestinal system.• Morphology: abundant acid-fast bacilli within macrophages; While Granulomas, lymphocytes, and tissue destruction are rare.
Leprosy: Leprosy, or Hansen disease, is a slowly progressive infection caused by Mycobacterium leprae, affecting skin and peripheral nerves and resulting in disabling deformities. M. leprae transmitted from person to person through aerosols from lesions in upper respiratory tract. Inhaled M. leprae, like M. tuberculosis, is taken up by alveolar macrophages and disseminates through blood, but grows only in relatively cool tissues of skin and extremities.
Pathogenesis: M. leprae is acid-fast obligate intracellular organism that grows very poorly in culture. Like M. tuberculosis, M. leprae secretes no toxins, and its virulence is based on properties of its cell wall. Leprosy has two patterns of disease: The less severe form, tuberculoid leprosy ,have asymmetric skin lesions. The more severe form, lepromatous leprosy, have symmetric skin lesions.
Patients with tuberculoid leprosy have a TH1 response, with production of IFN-γ. As with M. tuberculosis, IFN-γ is critical to cause an effective host macrophage response. Patients with lepromatous leprosy have a defective TH1 response; but a dominant TH2 response, which suppress macrophage activation in response to M. leprae.Morphology:Tuberculoid leprosy: Begins as localized skin lesions that are at first flat and red; then enlarge with irregular shapes and indurated, elevated, hyperpigmented margins and depressed pale centers (central healing). Neuronal involvement dominates tuberculoid leprosy.
On microscopic examination:• 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.Lepromatous leprosy: involves skin, peripheral nerves, anterior chamber of eye, upper airways (down to larynx), testes, hands, and feet. lesions contain large aggregates of lipid-laden macrophages (lepra cells) often filled with masses of acid-fast bacilli seen by modified ziehl neelsen stain. No granuloma.
SPIROCHETES :Spirochetes are Gram-negative, slender , corkscrew-shapedbacteria with axial flagella .Syphilis: chronic venereal disease caused by Treponema pallidum ( microaerophilic spirochete). T. pallidum is visualized by silver stains, dark-field examination, and immunofluorescence techniques. Sexual intercourse is usual mode of spread. Transplacental transmission occurs readily, and active disease during pregnancy results in congenital syphilis. Syphilis is divided into three stages:
Primary Syphilis:• occurring 3 weeks after contact with an infected individual.• as single ,firm, non tender, raised, red lesion (chancre) located at site of treponemal invasion on penis, cervix, vaginal wall, or anus.• The chancre heals in 3 to 6 weeks with or without therapy.• Spirochetes are plentiful within the chancre. Secondary Syphilis:• occurs 2 to 10 weeks after primary chancre in 75% of untreated patients.• The skin lesions occur on palms or soles , may be maculopapular, scaly, or pustular.
• Moist areas of skin, such as anogenital region, inner thighs, and axillae may have condylomata lata which are broad-based elevated plaques.• Silvery-gray superficial erosions of mucous membranes in mouth, pharynx, and external genitalia.• All these painless superficial lesions contain spirochetes and so are infectious.• Lymphadenopathy, mild fever, malaise, and weight loss are also common in secondary syphilis.• The symptoms of secondary syphilis last several weeks, after which the patient enters the latent phase of disease.
Tertiary Syphilis:• occurs in one-third of untreated patients, usually after a latent period of 5 years or more.• Tertiary syphilis has three main manifestations: cardiovascular syphilis, neurosyphilis and so-called benign tertiary syphilis.• These may occur alone or in combination.• benign tertiary syphilis is characterized by formation of Gummas in various sites.• Gummas are nodular lesions probably related to development of delayed hypersensitivity to bacteria.• Gummas occur most commonly in bone, skin, and mucous membranes of upper airway and mouth.
Serologic Tests for Syphilis: Include: Non treponemal tests:• measure antibody to cardiolipin (a phospholipid present in both host tissues and T. pallidum ).• These antibodies are detected in Rapid Plasma Reagin (RPR) , and Venereal Disease Research Laboratory (VDRL) tests. Treponemal antibody tests :• measure antibodies reactive with T. pallidum.• include Fluorescent Treponemal Antibody Absorption test (FTA-Abs) , and MicroHemaggluination Assay for T. Pallidum antibodies (MHATP).
Morphology:primary syphilis: The chancre contains an intense infiltrate of plasma cells, scattered macrophages and lymphocytes , and a proliferative endarteritis . The endarteritis is seen in all stages of syphilis. The regional lymph nodes may show nonspecific acute or chronic lymphadenitis, plasma cell-rich infiltrates, or focal epithelioid granulomas.secondary syphilis: mucocutaneous lesions show the same plasma cell infiltrate and obliterative endarteritis ,although the inflammation is less intense.Tertiary syphilis : The aortitis is caused by endarteritis of vasa vasorum of proximal aorta.
Higher magnification view of the syphilitic chancre shows an infiltrate composed of plasma cells, histiocytes, and lymphocytes. The findings are non-specific; however, a combination of endarteritis and plasma cell infiltrate should point to diagnosis
Syphilitic gummas are white-gray and rubbery, occur singly or multiply. On histologic examination, gummas contain a center of coagulated necrotic material and margins composed of plump or palisaded macrophages and fibroblasts surrounded by large numbers of mononuclear leukocytes, chiefly plasma cells. Treponemes are scant in gummas and are difficult to demonstrate.
Pathogenesis: The immune response to T. pallidum reduces the burden of bacteria, but it may also have a central role in pathogenesis of disease. The T-helper cells that infiltrate the chancre are TH1 cells which activate the macrophages to kill bacteria , and cause resolution of local infection. Although there are many plasma cells in syphilitic lesions and treponeme-specific antibodies are readily detectable, the antibody response does not eliminate the infection.