Tuberculosis & Leprosy

Tuberculosis & Leprosy

1. Pathological Lesion in Tuberculosis and Leprosy Lecture- 42

2. Learning Objectives Identify the morphology of granulomatous lesions produced by tuberculosis and leprosy

3. Part A Tuberculosis

4. Types of Tuberculosis A- Pulmonary Tuberculosis Primary Pulmonary Tuberculosis Secondary Pulmonary Tuberculosis B- Extrapulmonary or Isolated organ Tuberculosis Involves ; intestine, lymph node, bone, skin, vertebrae (Pott disease ) meninges, kidney , adrenals, testis, ovaries , fallopian tubes and epididymis C- Miliary Tuberculosis Pulmonary miliary tuberculosis Systemic miliary tuberculosis

5. Primary Pulmonary Tuberculosis Primary/ Ghon Complex Initial focus of infection a small subpleural granuloma about 10 mm in diameter with caseous granulomas in draining hilar lymph nodes Fibrocalcific nodule Primary lesion get organized, leaving a fibrocalcific nodule, however, TB bacilli may persist as viable organism for years Miliary TB In immunocomprised patient primary pulmonary TB would leads to miliary TB 5

6. Secondary Pulmonary Tuberculosis R eactivation of old primary infection or by reinfection Lesions nearly always located in the lung apices, sometimes bilaterally, and are about 30 mm in diameter, cavitation can occur at clinical presentation. Histologically C hronic caseous granulomatous inflammation Progression of disease Depends on the balance between host sensitivity and organism virulence Most lesions, converted to fibrocalcific scars

7. Extrapulmonary or Isolated Organ Secondary Tuberculosis Dissemination of TB outside of lungs can lead to TB of tonsils, intestine, CNS, Kidney, bone , skin and genital organs Miliary Tuberculosis: May be a consequence of either primary or secondary TB when resistance to infection is particularly poor, a "miliary" pattern of spread can occur in which small millet seed (1-3 mm) sized granulomas develops either in lung or in other organs Mantoux test is frequently negative

8. Pathogenesis of Tuberculosis

9. Pathogenesis of Granuloma Formation Type IV   hypersensitivity   or delayed type hypersensitivity  as the reaction takes several days to develop. Unlike the other types, it is not  antibody -mediated but rather is a type of  cell-mediated  response. The term delayed is used to differentiate a secondary cellular response, which appears 48-72 hours after antigen exposure, from an immediate hypersensitivity response, which generally appears within 12 minutes of an antigen challenge. These reactions are mediated by T cells and monocytes/macrophages rather than by antibodies. They are also termed type IV hypersensitivity reactions. CD4 +  T h 1  helper T cells  recognize antigen in a complex with the  MHC class II   major histocompatibility complex  on the surface of  antigen-presenting cells . These can be  macrophages  that secrete  IL-12 , which stimulates the proliferation of further CD4+ T h 1 cells. CD4+ T cells secrete  IL-2  and  interferon gamma , inducing the further release of other T h 1  cytokines , thus mediating the immune response. Activated  CD8+  T cells destroy target cells on contact, whereas activated macrophages produce  hydrolytic enzymes  and, on presentation with certain intracellular  pathogens , transform into  multinucleated giant cells . Delayed hypersensitivity reactions are inflammatory reactions initiated by mononuclear leukocytes. 9

10. Morphology of TB Granulomas Active Lesions; granulomatous reaction which comprises of: Nodular collection of epithelioid cells With or without central caseation necrosis Langhans type of giant cells (multiple nuclei arranged in a horse-shoe pattern) Circumferential collar of lymphocytes Old Lesions; Granulomas enclosed by rim of fibroblasts When healed, get fibrocalcifed

11. Non Caseating and Caseating Granulomas

12. Tuberculosis and HIV infection In the absence of appropriate T cell-mediated immunity granulomatous host response does not occur The intracellular bacteria persist and even proliferate within the macrophages Mycobacterium avium infection in a patient with AIDS, showing clumps of acid-fast organisms

13. Clinical Manifestations of TB Clinical Features Systemic manifestations are produced by TNF- alpha and IL -1 released from activated macrophages Fever (low grade, remittent, appear late each afternoon and then subside) Night sweats Malaise Anorexia Cough, first mucoid, later purulent and bloody sputum Pleuritic chest pain

14. Role of Pathologist in Diagnosis of TB Sputum Examination : Smears stained with Z-N examined, under oil immersion lens, bacilli appear as red rods FNA – enlarged lymph node Biopsies - Pleura , Lymph nodes, Lung and other tissues 14

15. Part B Leprosy

16. Leprosy Primarily a granulomatous disease of the peripheral nerves and mucosa of upper respiratory tract Etiology : Causative agent: Mycobacterium leprae In 2009 WHO classify leprosy simply based on the number of ( M. leprae bacilli ) in skin lesions; Paucibacillary leprosy: skin smear from skin lesions shows no leprae bacilli Multibacillary leprosy: skin smear from skin lesions shows M. leprae bacilli Clinically classified on the basis of increasing severity of symptoms: Tuberculoid leprosy (host with high resistance) Borderline tuberculoid leprosy Borderline leprosy Borderline lepromatous leprosy Lepromatous leprosy (host with low resistance ) * Indeterminate when not sure

17. Pathophysiology Lepromatous form In affected individual with defective T cell immunity, in contrast excessive B cell response, increase gamma globulin Histiocytes in deep dermis and shedding   epithelium shows large numbers of bacilli Skeletal changes frequent; like claw-hand or flat foot In advanced leprosy, destruction of sensory nerves with loss of sensations and circulatory alterations lead to slowly progressive atrophy of terminal phalanges and degenerative arthritis

18. Pathophysiology Tuberculoid form In affected individual with a relatively high state of natural immunity D isease is confined to the nerves and the skeletal changes less frequent Neurotrophic changes may regress but may progress

19. Tuberculoid leprosy Hypopigmented macules, some become anesthetic due to early neural involvement Cell mediated immunity well developed, granulomatous inflammation , scanty bacilli Spontaneous resolution in a few years or persists and progress to other forms Lepromin test: positive Borderline Tuberculoid Leprosy Smaller and more numerous lesions with less nerve enlargement May persist, revert to tuberculoid leprosy, or advance to other forms

20. Borderline Leprosy Many asymmetrically distributed, reddish plaques, moderately anesthetic, with regional lymphadenopathy May persist or regress, often progress to lepromatous type Borderline Lepromatous Leprosy Many skin lesions with macules (flat lesions) papules (raised bumps), plaques, and nodules, sometimes with or without anesthesia May persist, regress or progress to lepromatous leprosy 2/16/19

21. Lepromatous L eprosy Early; hypopigmented macules with no sensory loss, lesions diffuse and symmetric, with loss of hair, eyebrows or eyelashes a nd disfiguring nodularity (Lepromas) of the skin Late; nerve involvement leads to anesthetic areas and limb weakness, advance cases aseptic necrosis occurs Does not regress to less severe forms Cell mediated immunity is markedly diminished no granulomas Sheets of foamy macrophages loaded with Z-N positive Lepra bacilli, l ymphoplasmacytic infiltrate Lepromin test: negative 2/16/19

22. Clinical Manifestations of Leprosy Runny nose Dry scalp Eye problems Skin lesions; hypopigmented lesions with decreased sensation, do not heal after several weeks to months Thickening of peripheral nerves and loss of sensation in fingers and toes Muscle weakness Flat nose due to destruction of nasal cartilage Skin smears or Nerve biopsy: show acid-fast bacilli with the Ziehl-Neelsen stain or the Fite stain

23. Complications of Leprosy Following complications can occur when diagnosis/treatment is either delayed or started late: Sensory loss (usually begins in extremities), injured body parts without awareness ; can lead to additional infections and poor wound healing Permanent nerve damage (usually in extremities) Muscle weakness Progressive disfigurement ( e.g ; eyebrows lost, disfigurement of the toes, fingers, and nose) Circulatory disturbances leads to aseptic gangrene

24. Assignment Q1. Draw a diagram of caseous and non- caseous granulomas. Q2. Why Montoux test is negative in miliary TB? Q3.Why wound healing is delayed in Leprosy? Q4. Why Lepromin test is positive in Tuberculoid and negative in Lepromatous leprosy? 2/16/19

25. References Reading : Robbins Basic Pathology, 10 th Edition ( 2017), By: Kumar, Abbas, Aster Web Path