Mycobacteria: Tuberculosis and Leprosy

1. Mycobacteria: Tuberculosis and Leprosy Rick Lin, DO MPH

2. Tuberculosis Epidemiology • Estimated 1.7 billion infected persons • 1/3 of world’s population • 10 million people in US • 12 million new cases per year w/ 3 million deaths • 4 million co-infected with HIV • ¾ live in sub-Saharan Africa • Incidence tied to poverty, unemployment, homelessness, AIDS and drug resistance • Multi-drug resistant disease (MDRTB) major problem

3. http://www.med.sc.edu:85/fox/tuber-map3.jpg

4. Tuberculosis Etiology • Mycobacterium tuberculosis (Tubercle bacillus, MTB), M. bovis, M. africanum and BCG • Immune response contains infection in majority • 5-10% of immunocompetent develop clinical disease • Rarely eradicated due to resistance to macrophage destruction, dormancy within granulomas • Dormant bacilli resistant to antimycobacterials • Immunosuppression often leads to clinical sx

5. Tuberculosis Etiology • MTB Surface Coat • Mycolic acid • Highly inflammatory • Stimulates Macrophages and T lymphs

6. Tuberculosis Symptoms • Pulmonary: • SOB • Sputum production • Systemic: • Fatigue • Malaise • Fever (in ddx for FUO) • Lethargy • Weight loss

7. Tuberculosis Symptoms • Disseminated Disease: • Miliary pattern on CXR • Pancytopenia • Other Sites: • Bones, GI, brain, meninges • Almost any organ • Asymptomatic in large number of persons • 90%

8. The Tuberculin Reaction • The Koch Phenomenon • Most likely due to a Delayed T-cell Hypersensitivy (DTH) rxn • Mediated by sensitized T lymphs when injected into a nonsensitized individual • In sensitized individual rxn varies depending on test dose and route of administration • Local intradermal inject. leads to the local TB rxn • Reaches max intensity after 48 hrs • Consists of a sharply circumscribed area of erythema and induration

9. The Tuberculin Reaction • Purified Protein Derivative (PPD) is currently used • Read 48-72 hours after intradermal injection • Becomes positive between 2 and 10 weeks and remains positive for many years http://www.info.gov.hk/dh/diseases/CD/photoweb/Tuberculosis-2.jpg

10. PPD evaluation • 0.1ml of PPD (5U) placed intradermally to form a wheal • Measure true induration (not erythema) 48-72 hrs • >5mm Induration is positive in following hosts: • patients with recent close contact with a person with active TB • patients with fibrotic lesions on chest radiograph • patients with known or suspected HIV infection • >10mm Induration is positive in: • Patients with high risk comorbid conditions • Persons from endemic areas • Residents of long-term (chronic) care facilities • >15mm required for positivity in normal hosts

11. TB Histopathology • Tubercle is the hallmark • Accumulation of epithelioid histiocytes with Langerhans giant cells • Caseation necrosis in the center • Rim of lymphs & monos • The tuberculioid granuloma is characteristic but NOT pathognomonic

12. This is a higher magnification of the tuberculous process illustrating specifically the multinuclear giant cells (g) or Langerhans cells with numerous adjacent histiocytes (h) or epithelioid cells. The epithelioid cells are the fat histiocytes which bear some resemblance to epithelial cells. The Langerhans giant cells possibly result from a coalescing of multiple histiocytes or perhaps even by incomplete mitotic division of reproducing histiocytes.

13. This frame shows caseation necrosis (c). There is none of the residual framework of the pre-existing tissue and the blue dots represent the nuclear debris from necrotic cells. The peripheral cells in the field are histiocytes (h).

14. BCG Vaccination • Bacillus Calmette-Guerin (BCG) is a living attenuated bovine tubercle bacillus to enhance immunity to tuberculosis • Only given to TB (-) persons • Reduces childhood TB up to 75% • Normal course of BCG vaccination • 2 wks: infiltrated papule develops • 6-12 wks: size of 10mm, ulcerates, and then slowly heals leaving a scar

15. Rare BCG Reaction

16. Primary Inoculation TB • 2-4 wks after inoculation painless brown-red ulcer with hemorrhagic base • 3-8 wks regional lymphadenopathy - painless • Face, hands, and legs • Histopathology • Typical tubercles • Langerhan’s cells w/ epithelioid cells surrounded by monocytes

17. Primary Inoculation TB • Course: • W/o tx may last up to 12 mo • Lesions heal by scaring • Primary TB complex usually yields immunity but reactivation my occur

18. Primary Cutaneous TB http://www.embbs.com/img/i0000005.jpg http://plaza.umin.ac.jp/~otaderma/pattern/nd/nd13.jpg

19. Tuberculosis Verrucosa Cutis • Exogenous reinfection of MTB in a person previously sensitized • Minor wound often site of entry • many cases in pathologists/ postmortem attendants - hence the expression “prosector’s warts” • PPD highly (+) http://dermis.net/doia/image.asp?zugr=d&lang=e&cd=21&nr=99&diagnr=17020

20. Tuberculosis Verrucosa Cutis • Usually a single slow-growing plaque or nodule m/c on hands • Small papule that becomes hyperkeratotic • Peripheral expansion w/ wo central clearing • Clefts and fissures discharging pus extend into the underlying base which is brownish-red to purplish

21. Scrofuloderma • TB involvement of the skin by direct extension • Usually underlying TB lymphadenitis • Cervial Lymph nodes MC • Develops as firm subcutaneous bluish-red nodules • Break down and perforate leaving undermined ulcers and discharging sinuses • Bilateral http://www.indianpediatrics.net/jan2002/images/7.jpg

23. Scrofuloderma • Histopathology: • Massive necrosis and abscess formation in the center • The periphery of the abscess or the margins of the sinuses contain tuberculoid granulomas and true tubercles • Acid-fast bacilli • MTB can be found

24. Tuberculosis Orificialis • TB of mucous membranes and skin surrounding orifices • Usually by autoinoculation • Seen in pts with TB of internal organs • GI Tract or Lungs • Mouth most commonly affected site • Tongue and palate • Prognosis poor – advanced internal disease • Presents as painful yellow or red nodule that ulcerates to form punched-out ulcer

25. Tuberculosis Orificialis • Histopath: • Massive nonspecific inflammatory infiltrate and necrosis • Tubercles with caseation may be found deep in the dermis • Numerous bacilli

26. Lupus Vulgaris • Cutaneous TB from hematogenous spread • Chronic and progressive • 50% have TB elsewhere • Single plaque of grouped red-brown papules that blanch with diascopic pressure • “Apple-jelly” nodules = pale brown/yellow • Spreads peripherally • Risk of BCC/SCC with mets • 90% occur head/neck http://dermatlas.med.jhmi.edu/derm/result.cfm?Diagnosis=-901045419

28. Lupus Vulgaris • Histopath • Hallmark: Classic Tubercles

29. Metastatic Tuberculous Abscess • Tuberculous Gumma • Hematogenous dissemination from primary focus during a period of lowered resistance leading to distant abscess/ulcer • SubQ abcesses • Nontender • Fluctuant • Singly or as multiples on the trunk, ext, or head • Usually occurs in undernourished children or the immunodeficient or immuosuppressed

30. Metastatic Tuberculous Abscess

31. Metastatic Tuberculous Abscess • Histo: • Similar to scrofuloderma • Massive necrosis and abcess formation • Acid fast stains = copious amounts of myocbacteria

32. Miliary TB (Miliaris Disseminata) • Hematogenous dissemination of MTB • Infants / young children • Focus of infection typically meningeal/pulmonary • May follow infections such as measles and HIV • Presentation: • Minute erythematous macules or papules and purpuric lesions • Sometimes umbilicated vesicles or a central necrosis and crust develop in severely ill patients

33. Miliary TB (Miliaris Disseminata) • Histopath: • Initially: • Necrosis and nonspecific inflam infiltrates and abcesses • Occasionally signs of vasculitis • MTB are present in and around vessels • Later stages (if the pt. develops immunity): • Lymphocytic cuffing of vessels and even tubercles

34. Miliary TB of the Liver Multinucleated Giant Cell

35. Tuberculids • Cutaneous immunologic rxn to TB elsewhere • By definition stains negative • Most likely the result of hematogenous dissemination in pts with high degree of immunity • With PCR, mycobacterial DNA demonstrated in both papulonecrotic tuberculid and erythema induratum of Bazin • All demonstrate rapid response to antiTB tx • Strongly positive PPD • Most exhibit tuberculois features histologically

36. Tuberculids • Lichen Scrofulosorum • Rare eruption of asymptomatic, minute, flat-topped yellow to pink follicular or parafollicular papules • May have a minute horny spine or fine scales • Occurs m/c on trunk of children and adolescents with TB in lymph nodes/bone • PPD (+) • Persist for months but spontaneous involution ensues • AntiTB tx results in resolution w/in weeks

37. Tuberculids • Lichen Scrofulosorum • Histopath: • Superficial noncaseating tuberculoid granulomas develop around hair follicles • Mycobacterium are not seen and can't be cultured

38. Tuberculids Papulonecrotic Tuberculid • Symmetric, necrotic papules that occur in crops over the extremities and healby scarring • Dusky red, symptomless, pea-sized papules • Usually seen in children or young adults • MTB DNA has been detected in about 50% of pts

39. Tuberculids Papulonecrotic Tuberculid • Histopath: • Wedge-shaped necrosis of the upper dermis extending into the epidermis • Involvement of blood vessels is a cardinal feature • Consists of an obliterative and sometimes granulomatous vasculitis leading to thrombosis and complete occlusion

40. Papulonecrotic Tuberculid Dusky red, pea sized papules that are symmetric and become necrotic

41. Tuberculids Erythema Induratum (Bazin’s Disease) • Dusky-red 1-2 cm tender nodules usually occurring on the lower legs in middle-aged women • Resolve spontaneously w or wo ulceration • The vessels of these pts react abnormally to changes in ambient temp • The eruptions assoc w/ exposure to cold • Active TB is found only rarely

42. Erythema Induratum www.emedicine.com Evidence of panniculitis exhibiting lobular, granulomatous, and lymphohistiocytic inflammation Nodules after resolving with ulceration

43. Atypical Mycobacteria Mycobacterium marinum • “Swimming pool/fish tank” granuloma • Ulcerating lesions in skin at site of abrasions incurred in swimming pools about 2-3 wks. after inoculation • Single nodules, typically on hands, may ulcerate and suppurate with sporotricoid ascending spread • Fresh and salt water • Tx with Minocycline 100 mg bid • Heals spont. w.in 1-2 yrs. w/residual scarring

44. Mycobacterium marinum Localized Necrosis Intracellular bacilli Acid fast bacilli stain of tissue infected with M. marinum

45. Atypical Mycobacteria Mycobacterium ulcerans infection • Buruli ulcer, Bairnsdale ulcer, Searl ulcer • Subequatorial regions of Africa, wet, marshy, swampy areas • Never found outside the human body • Incubation period of ~3 mo • Painless subq swelling which enlarges to a nodule that ulcerates • Ulcer is deeply undermined and necrotic fat is exposed exposing muscle and tendon

46. Atypical Mycobacteria Mycobacterium ulcerans infection • Histo- Central necrosis in the interlobular septa of the subcut. fat, surrounded by granulation tissue w/giant cells but no typical caseation necrosis or tubercles. AF orgs. can always be demonstrated. • TX- Excision of early lesion. Local heat, hyperbaric oxygen and chemo w/RIF and Bactrim.

47. M. ulcerans http://www.cdc.gov/ncidod/eid/vol5no3/dobos.htm In A, arrows indicate necrosis of adipose tissue distant from the location of AFB, and in B, the arrow indicates predominance of extracellular bacilli and microcolonies

48. Atypical Mycobacteria Mycobacterium kansasaii • Unusual skin pathogen more commonly associated with pulmonary disease in middle-aged men • Infections localized to Midwestern states and Texas • Acquired from the environment • Variable skin presentations: • Nodules • Plaques • Crusted ulcers m/c in immuno-suppressed • Responsive to anti-TB tx: Streptomycin, Rif, Emb • Atypical mycobacterium most closely related to MTB

49. Atypical Mycobacteria • Mycobacterium avium complex (MAI/MAC) • M. avium and M. intracellulare infects lungs and lymph nodes but occasionally causes cutaneous lesions with dissemination • Single or multiple painless, scaling, yellowish plaques w/ a tendency to ulcerate • Common in AIDS • Highly resistant to anti-TB drugs requiring several in combination: • Azithromycin, Rifampin, Ethambutol • Where feasible surgical tx is advisable • Rifampin used for prophylaxis

50. http://meds.queensu.ca/~medpalm/PDA_Portal/case11.html Mycobacterium avium Mycobacterium intracellulare