Your SlideShare is downloading. ×
cutaneous tuberculosis
Upcoming SlideShare
Loading in...5
×

Thanks for flagging this SlideShare!

Oops! An error has occurred.

×

Saving this for later?

Get the SlideShare app to save on your phone or tablet. Read anywhere, anytime - even offline.

Text the download link to your phone

Standard text messaging rates apply

cutaneous tuberculosis

2,577
views

Published on

history of TB,epidemiology, clinical features, lab diagnosis, treatment, MDR TB, XDR TB, TDR TB, and mechanism of drug resistant, methods of identification of resistant drugs

history of TB,epidemiology, clinical features, lab diagnosis, treatment, MDR TB, XDR TB, TDR TB, and mechanism of drug resistant, methods of identification of resistant drugs


0 Comments
3 Likes
Statistics
Notes
  • Be the first to comment

No Downloads
Views
Total Views
2,577
On Slideshare
0
From Embeds
0
Number of Embeds
0
Actions
Shares
0
Downloads
246
Comments
0
Likes
3
Embeds 0
No embeds

Report content
Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
No notes for slide

Transcript

  • 1. CUTANEOUS TUBERCULOSIS BY : Dr. Daulat ram dhaked
  • 2. Introduction Mycobacterium tuberculosis • Term „mycobacterium‟ was given in 1896 to a large group of bacteria producing mould-like pellicles when grown on liquid media • Weakly gram-positive, strongly acid fast, aerobic, nonspore forming, nonmotile, facultative, intracellular, curved rods measuring 0.2-0.5 X 2-4 um. • Cell wall contains mycolic acid-rich, long-chain glycolipids and phospholipoglycans (mycocides) • Protect mycobacteria from cell lysosomal attack • These compounds retain red carbol fuchsin dye after acid decolorization & are responsible for acid-fast staining of Mycobacteria.
  • 3. • Typical tubercular lesion is epithelioid granuloma with central caseation necrosis • Early tubercles are spherical 0.5- to 3-mm nodules with 3 or 4 cellular zones 1. Central caseation necrosis, 2. Inner cellular zone of epithelioid macrophages and Langhans giant cells admixed with lymphocytes, 3. Outer cellular zone of lymphocytes, plasma cells, and immature macrophages, and 4. Rim of fibrosis in healing lesions.
  • 4. Introduction CUTANEOUS TUBERCULOSIS • First description by • – Laennec in 1826 • – prosector’s wart sustained while performing an autopsy on a patient with spinal TB • 1/3rd world’s population infected with Mycobacterium tuberculosis bacteria • Incidence is low as compared to pulmonary tuberculosis. • In India cutaneous manifestations of TB (including tuberculids) are found in < 0.1% of individuals seen in dermatology clinics. • Cutaneous TB- 1.5% of extrapulmonary TB
  • 5. Epidemiology • Childhood TB – 5-15% of all cases of TB – most commonly in 10-14 years of age • Commonest form – in adults: Lupus Vulgaris – in childhood: Scrofuloderma and Lichen scrofulosorum
  • 6. Epidemiology • 70% developed disease in spite of being vaccinated with BCG • Male:female = 1.3:1. • Most patients show clinical infection within first 3 decades of life. • Female preponderance in scrofuloderma • M. bovis found in 1–1.5%
  • 7. Immunopathology • Skin biopsy specimens examined with monoclonal antibodies – intense expression of HLA-DR on keratinocytes – moderate to high Langerhans cell hyperplasia – infiltration by CD3+ pan-T cells as well as CD8+ and CD4+ T cells(CD4 > CD8) • Predominant lymphocyte in dermal granulomas – activated CD3+ T cell – expressing MHC class II antigens & interleukin 2 receptor
  • 8. Classification Route of infection Clinical type histology course Tuberculosis chancre Tuberculosis verrucoasa cutis Lupus vulgaris (occasionally) Non specific TB specific TB specific Localized Localized Localized Secondary tuberculosis ( endogenous source) Contiguous spread Scrofuloderma TB specific Localized Auto-inoculation Orificial tuberculosis TB specific Progressive Haematogenous tuberculosis Acute military tuberculosis Lupus vulgaris Tuberculous gumma TB specific TB specific TB specific Generalized Localized Localized Lichen scrofulosorum Variable Localized Papular or papulonecrotic tuberculid variable Scattered Crops Generalized Inoculation tuberculosis (exogenous source) Eruptive tuberculosis (Tuberculids) Micropapular Papular Nodular variable Erythma induratum of Bazin
  • 9. Classification • Not previously exposed • Multibacillary  Primary inoculation – Tuberculosis chancre TB, scrofuloderma, tuberculosis – Milliary tuberculosis of the skin periorificialis, acute military • Previously sensitized hosts tuberculosis, gumma – Lupus vulgaris • Paucibacillary – Scrofuloderma Tuberculosis verrucosa cutis, lupus vulgaris – Tuberculosis verrucosa cutis
  • 10. Lupus vulgaris 1808, Robert willan Founder of british derma. Gave term LUPUS To nodular eruption on face 1887, William Tilburg Fox used term LUPUS VLGARIS for skin TB LUPUS word Origin ? Latin word of wolf ? Greek word lepros
  • 11. Clinical features • • • • Lesions usually solitary > 90% involve head and neck in western countries. In India, Mostly in lower half of the body Characteristic lesion plaque, border composed of soft, reddish-brown papules • Small, reddish-brown, flat plaque of soft, gelatinous consistency • Elevated, infiltrated, brown, discoid with areas of atrophy • Central healing with scarring while periphery continues to spread
  • 12. Clinical features • Morphological variants – classic plaque or keratotic type (most common) – hypertrophic – ulcerative – atrophic – Planar • Miliary lupus – multiple papules/nodules occur simultaneously in disseminated lupus – occurs after temporary immunosuppression, such as after viral infections • Unusual presentations – sporotrichoid pattern – site of BCG vaccination – vicinity of Scrofuloderma
  • 13. Clinical features • Mucosal lesions – Nasal, buccal or conjunctival mucosa – Nasal lesions start as nodules, bleed easily, ulcerate, leading to cartilage destruction – Early symptom dry rhinitis – Can produce stenosis of the larynx and scarring deformities of the soft palate • Complications – Scarring, contractures and tissue destruction – Squamous cell and basal cell carcinomas
  • 14. Diascopy test: If lesion is pressed by a glass slide to diminish vascular component of inflammation, individual nodules appear as yellow brown spots (apple jelly color), so nodules are named “apple jelly nodules”.
  • 15. Histopathology • Epidermal atrophy, ulceration, or hyperplasia showing Acanthosis, Hyperkeratosis, Papillomatosis • Destruction of cutaneous appendages • Inflammation more prominent in upper dermis • Epitheloid cells tuberculoid granulomas • Giant cells (usually of langhans type) with slight or absent caseation necrosis within the tubercle • Infiltrate of lymphocytes may be so prominent that the granulomatous component obscured • Margins of ulcers pseudoepitheliomatous hyperplasia • Without deep biopsy diagnosis may be missed
  • 16. Scrofuloderma (Tuberculosis colliquativa cutis) 1883, Ernest Besnier wrote about scrofulous gumma Latin word scrofa means a breeding sow, b/c swine were supposed to be subject to the complaint
  • 17. Clinical features • Involvement of skin overlying contiguous tuberculosis focus usually in lymph gland, bone, joint, lacrymal gland or duct • Bluish-red nodule breaks down to form undermined ulceration with granulating tissue at base • Scarring and fibrosis of lymph nodes may lead to lymphoedema and elephantiasis • Skin of the lymphoedematous area may show lesions of cutaneous TB, usually lupus vulgaris • Numerous fistulae may intercommunicate beneath ridges of a bluish skin
  • 18. Histopathology • Center of lesion abscess formation or ulceration • Deeper portions and at periphery – Diffuse dense mixed cell infiltrate of neutrophils, some eosinophils, plasma cells, lymphocytes and histiocytes • Tuberculoid granulomas with caseation necrosis seen in most cases
  • 19. Warty tuberculosis Synonyms: Tuberculosis verrucosa cutis Anatomist’s warts Prosector’s warts Verruca necrogenica
  • 20. Clinical features • • • • • Accidental superinfection Physicians, pathologists and post-mortem attendants Autoinoculation with sputum Lower limbs most common site for warty TB in children Lymphadenopathy not seen in contrast to Scrofuloderma and Lupus vulgaris
  • 21. Clinical features • Small, symptomless, indurated, warty papule with slight inflammatory areola • Extends to form verrucous plaque • Irregular extension at edges leads to serpiginous outline • Involution of centre forming white atrophic scar • Firm and purplish, red or brown • Skin biopsy from least keratotic area and incised deep enough to include the underlying indurated plaque
  • 22. Histopathology • Hyperkeratosis and Acanthosis • Acute inflammatory infiltrate • Abscess formation in upper dermis or within downward extensions of epidermis • Mid-dermis tuberculoid granulomas with necrosis
  • 23. Primary inoculation tuberculosis • Earliest lesions – 2–4 weeks after inoculation – brownish papule, nodule, or ulcer with an undermined edge and granular haemorrhagic base • Edge firm with adherent crust • Painless, non-healing ulcer or lesion with localized lymphadenopathy, especially in child, should arouse suspicion
  • 24. Haematogenous tuberculosis • Miliary tuberculosis • Usually affects – Young children – Immunosuppressed patients – Concurrent HIV infection – Following viral infections • ill patient develops – Crops of minute bluish papules, vesicles, pustules – Erythematous nodules – Haemorrhagic lesions
  • 25. Haematogenous tuberculosis • Diagnosis sometimes made by biopsy of skin lesion showing acid-fast bacilli • Histopathology papule shows a microabscess containing Neutrophils, cellular debris, numerous tubercle bacilli surrounded by zone of macrophages
  • 26. Orificial tuberculosis • More common in males with impaired cell mediated immunity • Most commonly in mouth • Diagnosis suspected when ulcer does not heal inspite of antibiotic therapy • Small oedematous red nodules rapidly break down to form painful, shallow ulcers with undermined bluish edges and do not heal spontaneously
  • 27. Orificial tuberculosis • Associated with granulomatous swelling of lips and may involve the tongue • Pain cardinal feature • Histopathology ulcer surrounded by nonspecific inflammatory infiltrate, tuberculoid granulomas with pronounced necrosis deep in dermis
  • 28. Metastatic tuberculous abscess (Tuberculous gumma) • Malnourished children, immunosuppressed patients, after local trauma and in association with underlying lymphoma • Firm subcutaneous nodule or fluctuant abscess most commonly on extremities • May break down to form an undermined ulcer often with sinuses • Histopathology caseation necrosis with rim of Eisinophils and Giant cells
  • 29. Unusual forms of cutaneous tuberculosis • Suspicion by – Painless abscess formation – Indolent ulcers with bluish undermined edges – Nodular, plaque-like or necrotic lesions that defy easy classification • Gangrenous or vegetating forms with underlying lung or glandular disease • Tuberculous cellulitis-like lesions reported in diabetic and on oral corticosteroids
  • 30. Congenital tuberculosis • Exceedingly rare • Discrete, erythematous lesions, with central necrotic dell in infants with febrile systemic illness
  • 31. Tuberculids • Darier in 1896 • Hypersensitivity reaction to M. tuberculosis or its products in patient with significant immunity • Following criteria must be fulfilled to designate a condition as tuberculid: – Skin lesion must show tuberculoid histopathology – Mycobacterium tuberculosis must not be demonstrated in the lesion – Tuberculin test must be strongly positive – Treatment of underlying TB focus must lead to resolution of skin lesion
  • 32. Lichen scrofulosorum • • • • Hebra in 1868 Second most common pattern of cutaneous TB in children Systemic focus of TB detected in majority cases Most commonly involve cervical, mediastinal or hilar lymph nodes • Symptomless, 0.5– 3.0 mm, closely grouped lichenoid papules • Skin-coloured, but may be yellowish or reddish-brown
  • 33. Lichen scrofulosorum • Perifollicular and appear in groups or in annular arrangement or plaques • Adherent crust or small pustule • Mainly found on the abdomen, chest and back, and proximal limbs • Antituberculous therapy, the lesions usually clear within 4–8 weeks without scarring
  • 34. Histopathology • Superficial dermal granulomas, usually in vicinity of hair follicles or sweat ducts • Granulomas composed of epithelioid cells, with some Langhans giant cells and narrow margin of lymphoid cells at periphery • Caseation necrosis absent
  • 35. Papulonecrotic tuberculid • Necrotizing papulonodular lesions of size 2 to 8 mm • Symmetrical crops • Preceded by fever and constitutional symptoms • Pustulation and crusting in centre and heal with varioliform scarring in 4-6 weeks • Sites of predilection legs, knees, elbows, hands and feet • Cases on glans of penis have been reported
  • 36. Papulonecrotic tuberculid • Young adults predominantly affected • Focus of TB can be demonstrated in 38 to 75% of patients • Transition to and coexistence with lupus vulgaris described • Association with erythema induratum
  • 37. Histopathology • Vascular involvement observed in early lesions • Leukocytoclastic vasculitis or lymphocytic vasculitis. • Associated with fibrinoid necrosis and thrombotic occlusion of individual vessels • Wedge-shaped area of necrosis with broad base toward epidermis • As wedge gradually cast off, epithelioid and giant cells gather around its periphery • Focal granuloma formation poor • Follicular necrosis or suppuration may occur
  • 38. Erythema induratum of Bazin • Main pathology in subcutaneous fat • Indolent, mildly tender, dull red nodules ranging in size from 5 to 7.5 cm • Usually develop on calves • Four times more common in women • Mycobacterial DNA can be found in up to 77% of skin biopsy specimens • Lesions may ulcerate • Precipitated by cold weather • Ragged, irregular and shallow ulcers with bluish edge • Commonest form of cutaneous tuberculosis found in Hong Kong
  • 39. Erythema Nodosum • Erytematous, tender, 2.5 to 5 cm nodules that usually develop on shins • May also involve the thighs, buttoks and forearm in severe cases • Low grade fever and swelling of ankle joints accompany the skin lesions in some patients • The lesions regress spontaneously becoming dull red, violaceous • Ulceration and scarring not the features • Skin biopsy reveals a septal panniculitis with no evidence of vasculitis
  • 40. Cutaneous tuberculosis in immuno-compromised • Risk of active tuberculosis in people co-infected with HIV and M. tuberculosis 3–8% per year and lifetime risk >50% • Ulceration and discharge from surface of lesion • Biopsy – neutrophilic infiltrate which may be admixed with histiocytes – Epithelioid cells, giant cells and well formed granulomas uncommon • AFB seen in large numbers • Culture usually grows Mycobacterium tuberculosis or NTM • 66% M. avium complex, 10% M. tuberculosis
  • 41. Laboratory Diagnosis Nucleic acid probes Nucleic acid sequencing
  • 42. Tuberculin skin test / Mantoux test • ID inj of purified protein derivative (0.1 ml (5TU) PPD) • Culture filtrate of tubercle bacilli containing over 200 antigens shared with bacille Calmette–Guérin (BCG) and many NTM • Positive test – Clinical or latent tuberculosis infection – Contact with environmental mycobacteria • Low sensitivity (false negative reactions) – Immunosuppressed patients – Patients with severe illness – Active tuberculosis – HIV infection – Immunosuppressant drugs
  • 43. Mantoux test • False-positive – exposure to environmental mycobacteria – within 1 year of BCG vaccination when administered in infancy • AIIMS study – doubtful diagnosis of cutaneous tuberculosis 79 – finally categorized as tuberculosis 39 – non-tuberculosis 16 – final diagnosis could not be reached 24 • Readings – cases 0 to 40 mm – non-cases 0 to 30 mm • sensitivity • specificity 58.97% 62.50%
  • 44. Interferon-γ assays • Detect latent tuberculosis infection measuring in vitro IFN-γ release in response to antigens highly specific for M. tuberculosis • Not confounded by previous bacille Calmette–Gue´rin vaccination, conferring higher specificity  Enzyme-linked immunospot (ELISpot) enumerates IFN-γ secreting T cells, FDA approved in july 2008,expected to replace TST, Sensitivity87.5%,specificity-86.7%  Whole-blood ELISA, QuantiFERON-TB Gold measures IFN-γ concentration in supernatant by enzyme linked immunosorbent assay (ELISA), Uses antigens ESAT-6,CFP-10 and TB7.7, Sensitivity81%,specificity-99.2%  Genes on Region of difference 1 (RDI1) of M. tuberculosis genome (deleted from genome of M.bovis BCG and certain NTM)
  • 45. Demonstration of AFB • Direct demonstration of organism in tissue smear or biopsy specimens by staining for AFB is practically of no value in diagnosis of skin TB
  • 46. Culture • L-J medium low rates of 8.8% to 10.7% positivity • Chennai study (3 solid media and 2 liquid media) – Total patients 213 – Culture positive in 112 (55%) – lupus vulgaris 60 of 106 (57%) – verrucosa cutis 40 of 73 (55%) – scrofuloderma 12 of 24 (50%)
  • 47. BACTEC system  Culture – 4 ml of Middlebrook 7H12 broth medium containing 14 C-labeled palmitic acid for radiometric detection  0.5 ml of processed specimen is added to broth.  Growth is ascertained by liberation of 14CO2 as metabolized by mycobacteria & detected by BACTEC 460 instrument & reported in terms of growth index (GI) value. – growth • BACTEC 62.8% • L-J medium 25.7% • combined 74.3% (26/35) – mean detection time • BACTEC 17.3 days • L-J medium 39.4 days
  • 48. Histopathology • Epithelioid cell granuloma 60 to 100 % • Recent series histopathology suggestive of tuberculosis – Total 175(86%) out of 202 – lupus vulgaris 82% – tuberculosis verrucosa cutis 90% – Scrofuloderma 95% • Caseation necrosis – Scrofuloderma all cases – Lupus vulgaris 3 of 108 – Tuberculosis verrucosa cutis none
  • 49. Immunohistochemistry • • • • • • • Fifty skin biopsy specimens – Z-N stain & by culture all negetive for AFB – Mycobacterial antigen present 68% – Scrofuloderma 89% – Lupus Vulgaris 69% – Tuberculosis Verrucosa Cutis 47% Mycobacterial antigen demonstrable in majority of cases of cutaneous tuberculosis using polyclonal antiserum • Cross reactivity reported in cases of leprosy and in some fungal infections
  • 50. Polymerase chain reaction • • • • • Victor et al first described use of PCR in cutaneous TB confirmation of M. tuberculosis – PCR 1-3 days – culture 2-6 weeks mycobacterial DNA demonstrated in – all different histopathological variants of cutaneous tuberculosis – two of tuberculids (papulonecrotic tuberculid and erythema induratum)
  • 51. DNA PCR rRNA PCR
  • 52. RNA PCR • mRNA contrast to DNA and rRNA – is rapidly degraded – t1/2 of 3 minutes – recently viable organism • Single-tube, nested, RT-PCR (STN RT-PCR) • For smear-negative samples (1 to 1,000 bacilli/ml) – sensitivity of PCR 83% – sensitivity of culture 75% – specificity of PCR 100%
  • 53. Treatment
  • 54. GLOBAL TB DRUG PIPELINE
  • 55. Treatment • WHO(2009) recommendations for cutaneous TB • HIV-negative individuals (adults as well as children) DOTS – intensive phase 4 drugs H, R, Z, E x 2 mths – continuation phase H and R x 4 mths • Daily dosing (2HRZE/4HR) recommended for all newly diagnosed • Alternatively – [2HRZE/4(HR)3]: daily intensive phase followed by 3/wkly continuation phase – [2(HRZE)3/4(HR)3]: 3/weekly dosing throughout therapy, provided every dose directly observed
  • 56. Drug therapy • HIV positive TB patients – same duration treatment as HIV-negative TB patients – Or TB patients living in HIV-prevalent setting should receive daily treatment, at least during the intensive phase – continuation phase, optimal dosing daily, 3/weeklydosing acceptable alternative • Ethambutol should be used in all pediatric cases, irrespective of age • If systemic focus is detected, corresponding disease categorization and recommendations should guide choice of drugs and duration of therapy
  • 57. DOTS • DOTS (directly observed treatment, short course) launched by WHO in 1995 – Cornerstone of global efforts at tuberculosis control – Category 3 regime under RNTCP abolished – Only 2 regimes in effect (of 1st line drugs) – Cat 1 for all new cases and Cat 2 for all retreatment cases – Cat 1: 2 H3R3Z3E3 + 4 H3R3 – Cat 2: 2 H3R3Z3E3S3+ 1 H3R3Z3E3 + 5 H3R3E3 • Culture and drug susceptibility testing (DST) for all previously treated TB patients at or before the start of treatment
  • 58. Drug therapy • DOTS-Plus – 5 or 6 medications inclusive of injectable drug and fluoroquinolone x 6 months – 4 oral drugs x 18 months • • phase II clinical trial: – Moxifloxacin increased proportion of sputum cultures that converted to negative, compared with ethambutol – Improvement in sterilization provided by moxifloxacin shortened treatment to 3 or 4 months in murine models of tuberculosis
  • 59. Treatment response • Safdarjang study from 1992-1997 • Total children 63 • Adhered to complete treatment 24 (6 months Lupus Vulgaris & 10 months Scrofuloderma) • Lupus vulgaris regressed markedly within 3 months, while Scrofuloderma took longer • Lymph nodes took longer to regress than skin lesions in Lupus vulgaris • 1 with widespread Lupus vulgaris who completed therapy relapsed after 18 months • patients failed to complete therapy 62%
  • 60. Multidrug-resistant (MDR) tuberculosis • Defined as resistance to rifampicin and isoniazid with or without resistance to other antituberculous drugs • MDRTB found in lupus vulgaris, scrofuloderma, and tuberculosis cutis • 3.6% of new and 20% previously tuberculosis (TB) patients in world have MDR-TB • Chennai study – Resistance to isoniazid either alone or in combination with other antituberculous drugs 7.2% – resistance to streptomycin 6.3% – multidrug resistant 2% • Line probe assay detect rifampicin and INH resistance M. tuberculosis • India low prevalence of MDR cases but high tuberculous burden
  • 61. Extremely drug-resistant (XDR) TB • XDR= HR + 1 FQ + 1 Injectable (KM or AMK or CM) • 10% of MDR-TB cases are also extensively drug-resistant (XDR-TB) • By September 2013, 92 countries had reported at least one XDR-TB case • Rifampicin resistance can be routinely detected by molecular probes on microscopy-positive or culture positive tissue • No other drug resistance can be routinely checked without susceptibility tests
  • 62. Mechanism of drug resistant • Natural or intrinsic drug resistance – Hydrophobic cell envelope that serves as a permeability barrier – Drug efflux systems and drug-modifying enzymes • Acquired drug resistance (drug resistance among previously treated patients) – – Most common type of resistance to first-line drugs (20), can emerge against any antituberculosis agent during chemotherapy • Primary drug resistance (drug resistance among new cases) – – Presence of drug-resistant organisms in a previously untreated person • Cross-resistance can occur between drugs that are chemically related and/or have same or similar target within mycobacterial cell • Mutations in genes encoding drug targets or drug activating enzymes are responsible for resistance, and point mutations and / or deletions have been found for all first-line drugs
  • 63. Identification of resistant drugs • Radiometric method (BACTEC) for first-line drugs • Proportion method for first-line drugs using solid media – Seeding of drug free and drug-containing solid media with equal Quantities Of two dilutions of a Standardized inoculum • Inhibition of growth • Mycobacteria Growth Indicator Tube (MGIT), as developed by BD Diagnostic, contains a modified 7H9 broth in conjunction with a fluorescence quenching-based oxygen sensor • Detection of metabolic changes – Viability assays based on use of indicator dyes (Pital and colleagues used resazurin) as an oxidation-reduction indicator – Flow cytometry, comparing DNA content and number of mycobacterial cells after 1 - 3 days in presence or absence of drug
  • 64. • Bacteriophage methods – Luciferase reporter mycobacteriophage technique has been shown to be capable of distinguishing drug-resistant from drugsusceptible strains of M. tuberculosis in a 48-h assay • Multiple methods for detection of mutations – Assays are based on DNA and RNA amplification method is used, most PCR – Hybridization, either with allele-specific nucleic acid probes or with peptide nucleic acid (PNA) probes in ELISAbased methods – Most rapid and powerful new method, real-time PCR, uses hybridization with fluorescence labeled probes • Oligonucleotide, or DNA, micro-arrays – Micro-arrays consist of a small solid surface made of glass, silicon, or other material that serves as a platform for anchoring a large collection of fragments of DNA (oligonucleotides on DNA chips, cDNA fragments on DNA arrays)
  • 65. Development of new vaccines • Several approaches to TB vaccine development have been made: • 1. ‘Improved’ BCG: e.g. over-expression of protective antigens (AGs), or reconstitution of deleted genes • 2. Attenuated Mycobacterium tuberculosis: targeted inactivation (‘knock-out’) of metabolic or virulence genes • 3. Adjuvanted Protein Subunit Vaccines (also peptides or DNA vaccines) – a. hypothesis driven selection: e.g. secreted AGs – b. empirical selection: e.g. T/B cell recognition and/or MHC binding, combination of AGs • 4. Other approaches: live-vectored AGs, e.g. vaccinia (MVP), adenovirus, Salmonella, etc or non-protein AGs, e.g. γd-TCR or CD1binding molecules; conjugates
  • 66. Immunotherapy • Administration of exoogenous IFNγ or IL-2 and other agents might augment host CMI responses, improve or accelerate clearance of tubercle bacilli • Immunomodulators such as: corticosteroids, HSP65DNA, TGFß inhibitors, HE2000, IL-4 inhibitors, intravenous immunoglobulin, rHuIFNγ, Eternacept therapeutic vaccines, and other drugs and biologics • Have potential to shorten treatment, by modulating the host response and helping the immune system eliminate persistent organisms. • Strategies studied to date in mouse models have been found to reduce Th2 inhibitory effect on protective Th1 response, either by inhibiting IL-4 production, or by downregulating Th2 response.
  • 67. VIT-D & TB • Niels Ryberg Finsen using a form of "concentrated light radiation “(Photobiomodulation) which won him a Nobel Prize. • "Introduced light cure for Lupus • In 2006, Liu and colleagues proved that Mycobacterium tubercolosis sensing by Toll-like receptor 2/1 (TLR2/1) complex increases expression of vitamin D receptors (VDR) and cYP27B1 in monocytes. • 1,25-dihydroxyvitaminD promotes VDR-mediated trans activation of antimicrobial peptide defensin-2 and cathelicidin (LL-37) and killing of intracellular Mycobacterium. • 4 µg/ml concentrations of vitamin D metabolites have been able in a reproducible way to protect infected human macrophages and restrict mycobacterial growth in vitro • Vit D protects against generation of autoimmunity. • It Inhibits T-helper (Th) 1 T cells response while conversely enhancing humoral Th2 cells response
  • 68. Nutrients & TB • Vit. A, Vit. E and Zinc are thought to have role in immune regulation • Adequate levels of ascorbic acid, proline and lysine can prevent MMP-9 secretion and degradation of collagen matrix in various systems. • AIIMS study, published in journal PLOS One, showing that vitamin C arrests growth of TB bacteria and sends them into a dormancy
  • 69. THANKS