Tuberculosis verrucosa cutis a skin condition

Tbvc

1. Cut. TB

2. Clinical spectrum Dependent on ? The route of infection Endogenous or exogenous The immune status of the patient and Previous sensitization with tuberculosis ±

3. Pathogenesis Pathogenic to humans ? Mycobacterium tuberculosis M. bovis - 1–1.5% Occasionally BCG - attenuated M. bovis Not a virulant organism

4. Transmission Inhalation Airborne droplet nuclei particles containing M. tuberculosis complex Resulting in pulmonary infection Penetration GIT mucosa and lymphatic tissue of the oro ‐pharynx M. bovis Direct inoculation of the skin M. tuberculosis complex - defect in the skin barrier

5. Survival of Mycobacterium species in aerosols generated from human saliva ? Less than 1 hour Prolonged contact is required for transmission of infection 1% of close contacts are affected

6. Predisposing factors Immunosuppression HIV infection Treatment with TNF‐α inhibitors Poverty, Malnutrition, Poor living conditions Drug resistant M. tuberculosis

7. Granuloma Dissemination of the bacteria takes place via the lymphatics & bloodstream In persons with intact immunity this initiates granuloma formation

8. RD1 locus Epithelial cell Macrophage

9. Granuloma RD1 locus in virulent mycobacteria releases the early secreted target 6 (ESAT‐6) protein Stimulates epithelial cells to produce metalloproteinase 9 (MMP‐9) MMP‐9 secretion promotes the recruitment of new macrophages to the granuloma New macrophages become infected and expand the granuloma . The host responds by producing CD4 & CD8 T cells that attempt to control bacterial growth

10. Pathogenesis Pathogenic to humans Mycobacterium tuberculosis M. bovis - 1–1.5% Occasionally BCG - attenuated M. bovis Not a virulant organism Why?

11. Genome RD1 - region of difference 1 RD1 is critical for bacterial virulence Absent in a genome of  Mycobacterium bovis  & BCG Encode the secretory proteins ESAT-6 (6-kDa early secreted antigen target) & CFP-10 (10-kDa culture filtrate protein)

12. Secretory protein

13. Granuloma Dissemination of the bacteria takes place via the lymphatics and bloodstream In persons with intact immunity this initiates granuloma formation Host ‐driven mechanism formed to control infection???

14. Granuloma Mature granuloma therefore represents? An equilibrium between mycobacterial growth and the host immune response M. tuberculosis can persist for decades within the granuloma

15. Overt tuberculous ? Early progression of a primary granuloma during the infection process or Reactivation of an established granuloma in a latently infected person Reactivation is usually due to ? Dysregulation in the immune response HIV infection, diabetes , cancer, malnutrition, ageing , TNF‐ α inhibitors

16. Primary tuberculosis ? Any lesions developing within 5 years of the original infection Secondary ? Later lesions Post ‐primary lesions are due to ? Reactivation of existing disease Reinfection Decreasing protection by BCG

17. Reactions in a host already sensitized by a previous infection differ from non‐sensitized Tuberculin test becomes positive after 3–8 weeks This may be accompanied by fever or erythema nodosum a sign of a recent primary infection

18. Histopathology Early, non‐specific inflammatory changes After 3–6 weeks Characteristic tubercle or granuloma Tubercle bacilli are rarely found Inoculation cultures may be positive

19. Granuloma Fully formed granuloma consists of ? A focus of epithelioid cells containing a variable, but usually sparse, number of Langhans giant cells A surrounding infiltrate of mononuclear cells The centre of the tubercle Undergoes caseation necrosis and sometimes calcifies As necrosis proceeds Endovascular or perivascular changes in the vicinity of the tubercle become more marked Accompanied by a cellular reaction leading to fibrosis

20. Caseous means? “cheese-like” in appearance The whitish appearance of the necrotic area

21. Necrosis? Coagulative necrosis Ischemia in most organs except the brain Liquefactive necrosis Cells are digested by hydrolytic enzymes – pus CNS Fat necrosis Liquefaction of the fat cells in peritoneal cavity Acute pancreatitis Fibrinoid necrosis Leakage of fibrin Due to the deposition of immune complexes in blood vessel walls Bright pink amorphous material

22. Caseation necrosis Peripheral rim of epithelioid histiocytes Peripheral rim of epithelioid histiocytes Multinucleated giant cells

23. Granulomas Vary in appearance Influenced by the virulence of the organism and the immune status of the patient Where cellular immunity is impaired Resulting pathology is less granulomatous Due to fewer activated macrophages Greater numbers of bacteria found

24. Granulomas Vary in appearance Influenced by the virulence of the organism and the immune status of the patient. Where cellular immunity is impaired Resulting pathology is less granulomatous Due to fewer activated macrophages Greater numbers of bacteria found

25. Sarcoidal granuloma

26. TBVC

27. Warty tuberculosis

28. The most common form of cutaneous tuberculosis in adults? Lupus vulgaris .

29. Warty tuberculosis Othetr names? Tuberculosis verrucosa cutis Anatomist’s warts Prosector’s warts and Verruca necrogenica Paucibacillary or multibacillary ? Paucibacillary

30. Warty tuberculosis Indolent, warty, plaque‐like form of tuberculosis Exogenous or endogenous? Caused by exogenous inoculation of M. tuberculosis into the skin Through open wounds or abrasions Sensitisation & Immunity? In previously infected or sensitized individuals Moderate or high degree of immunity

31. Exogenous inoculation ? Accidental inoculation from extraneous sources Autoinoculation with sputum in a patient with active tuberculosis Persons walking barefoot

32. Pseudoepitheliomatous hyperplasia Intense, mixed infiltrate

33. Histopathology Pseudoepitheliomatous hyperplasia with superficial abscess formation The intense, mixed infiltrate may show only sparse tuberculosis foci Bacilli are seen only occasionally

34. History? Slowly enlarging lesion Site ? Areas exposed to trauma and to infected sputum Hands, knees, ankles and buttocks

35. Clinical Asymptomatic Start as a small, indurated , warty papule with a slight inflammatory areola. By gradual extension, a verrucose plaque is formed. Irregular extension at the edges leads to a serpiginous outline with finger‐like projections The centre may involute , leaving a white atrophic scar Whole lesion may form a massive, infiltrated, papillomatous excrescence

36. Clinical The colour ? Purplish, red or brown Consistency ? Generally firm, but there may be areas of relative softening. Pus may be expressed from these soft areas or from fissures. Variation in appearance? Resemble lupus vulgaris - but the sites are different Appearance may be psoriasiform or keloidal Exudate and crusting may be predominant. Sporotrichoid spread Very rare - multiple lesions implying multiple inoculations Tuberculous lymphadenitis can occur

37. Clinical variants ? Deeply destructive papillomatous and sclerotic forms May cause deformity of the limbs A generalized form Ass. with papulonecrotic & lupoid lesions Exuberant granulomatous form

38. Differential diagnosis Warts Subungual and digital lesions Keratoses Lesion on hands Exuberant forms Blastomycosis , chromoblastomycosis and actinomycosis Leishmaniasisis Crusted lesions

39. Differential diagnosis Central scarring is surr. by a serpiginous edge Tertiarysyphilis Hypertrophic lichen planus and lichenification Multiple or itchy

40. Disease course and prognosis ? Extension is usually extremely slow Lesions may remain virtually inactive for months or years Spontaneous remission may occur and usually results in atrophic scars Responds to antituberculosis treatment

41. Investigations Histopathology Commercial IFN‐γ assays Help to differentiate lesions due to NTM and M. bovis PCR may be helpful if positive

42. Lupus vulgaris

43. Lupus vulgaris Paucibacillary or Multibacillaary ? Paucibacillary Sensitisation & Immunity? In previously infected or sensitized individuals High degree of immunity

44. Lupus vulgaris Chronic , progressive, paucibacillary form of cutaneous tuberculosis, occurring in a previously sensitized individual with a high degree of immunity to tuberculin

45. Causative organisms? Mycobacterium tuberculosis Mycobacterium bovis BCG The most common form of cutaneous tuberculosis in adults

46. Lupus vulgaris Presentation? Plaque, composed of soft, reddish brown papules, the appearance on diascopy being said to resemble apple jelly Exogenous or endogenous? Haematogenous or lymphatic spread from an underlying tuberculous focus Direct innoculation Complication of BCG vaccination

47. Lupus vulgaris Slowly enlarging plaque with an elevated border and central atrophy The edges of the lesion gradually extend in some areas and heal with scarring in others May cause considerable tissue destruction Clinical variants Tumour like Ulcerated form

48. Pathophysiology Originates from an underlying focus of tuberculosis - bone, joint or lymph node Commonly appears in normal skin as a solitary lesion It can arise at the site of a primary inoculation Tattoo, scar of scrofuloderma or site of a BCG Buttocks and trunk In children lesions - Lower limbs and buttocks

49. Pathology Histological features are variable Tubercles with scanty or absent central caseation Surr. by epithelioid histiocytes and multinucleate giant cells Seen in the superficial dermis Peripheral lymphocytes are often prominent. Occasionally, tubercle bacilli may be numerous The epidermis may be ulcerated with an associated mixed inflammatory infiltrate, atrophic or acanthotic If acanthosis is severe- pseudoepitheliomatous hyperplasia DD- SCC

50. Progression Small, reddish brown, flat plaque of soft, almost gelatinous, consistency. On diascopy , the diagnostic ‘apple jelly’ nodules Gradually becomes elevated, infiltrated and brown Grows by slow peripheral extension to become gyrate or discoid in shape with areas of atrophy Usually only a single lesion In disseminated forms with active pulmonary tuberculosis - multiple

51. Clinical patterns Plaque form Ulcerative & mutilating forms Tumour ‐like forms Papular & nodular forms

52. Plaque form Flat plaques with irregular or serpiginous edge The surface may be smooth or covered with psoriasiform scale Large plaques may show irregular areas of scarring with islands of active lupus tissue The edge often becomes thickened and hyperkeratotic

53. Clinical patterns Ulcerative & mutilating forms Scarring and ulceration predominate. Crusts form over areas of necrosis. The deep tissues and cartilage are invaded. Contractures and deformities occur. In milder form Keratotic plugs overlying pinpoint ulcers are associated with slow scar formation.

54. Clinical patterns Vegetating form Marked infiltration, ulceration and necrosis with minimal scarring. Mucous membranes are invaded and cartilage is slowly destroyed. When the nasal or auricular cartilage is involved Extensive destruction and disfigurement.

55. Clinical patterns Tumour ‐like forms Hypertrophic form Presents either as Soft tumour ‐like nodules or Epithelial hyperplasia with production of hyperkeratotic masses. In the ‘ myxomatous ’ form Huge soft tumours occur predominantly on the ear lobes, which become grossly enlarged Lymphoedema & vascular dilatation are sometimes marked.

56. Clinical patterns Papular & nodular forms Multiple lesions occur simultaneously in disseminated lupus‐true ‘ miliary lupus’ Usually occurs after temporary immunosuppression Post exanthematous forms, such as after measles

57. Mucosal involvement Nasal, buccal or conjunctival mucosa Primary - papule, nodule or ulcer, or Spread from a contiguous skin lesion Nasal lesions Start as nodules, which bleed easily Then ulcerate, leading sometimes to cartilage destruction. Dry rhinitis may be an early symptom.

58. Mucosal involvement Buccal mucosa, palate, gingiva or oro ‐pharynx Granulating, vegetating or ulcerating lesions By direct extension or by lymphatic spread from nasal lesions These can produce stenosis of the larynx and scarring deformities of the soft palate.

59. Differential diagnosis In the early stage Lymphocytoma , Spitz naevus or lupus erythematosus Syphilis Deep mycoses Lupoid form of leishmaniasis On the face Rosacea Port ‐wine stain Other mycobacterial infections

60. Differential diagnosis Leprosy and sarcoidosis Nodules of sarcoidosis resemble grains of sand Psoriasis More infiltrated and usually solitary (Lupus vulgaris ) Bowen disease Perianal area Lichen simplex chronicus and Crohn disease

61. Complications and co‐morbidities Scarring, contractures and tissue destruction Scars Thin, white and smooth, but are unstable May break down or become keloidal Contraction may lead to ectropion or microstomia Active lupus vulgaris frequently reappears in scar tissue Malignant changes Squamous cell carcinomas-25–30 years to develop Basal cell and syringoid eccrine carcinomas and Melanomas, lymphomas and sarcomas

62. Disease course and prognosis Natural course of an untreated lesion ? Progressive With appropriate treatment ? Clinical response as early as 5 weeks Marked improvement by 10 weeks Failure to respond within 4–6 weeks ? Suggest an alternative diagnosis

63. Investigations Skin biopsy AFB – Negative Culture PCR Tuberculin test is usually positive IFN‐γ assays may also be helpful

64. Diagnostic tests Clinical features & typical histological findings Absolute criterium Demonstration of M. tuberculosis Tissue culture from skin biopsy or cytological smear, or Demonstration of mycobacterial DNA by PCR

65. Other indicators of diagnosis Active, proven tuberculosis elsewhere The presence of AFB in the lesion itself This will also be seen in infections with other mycobacteria A strongly positive tuberculin reaction of >15 mm Positive IFN‐γ release assay The effect of therapeutic trial of ATT

66. Nucleic acid amplification tests In vitro amplification of specific DNA sequences using PCR Assay based on the insertion sequence IS 6110 Repetitive nature of IS 6110 in M. tuberculosis genome Other gene targets 16s rRNA gene Genes encoding MPB‐64, 38 kDa and 65 kDa proteins Multiplex PCR Combination of two or more gene targets IS6110 + MPB‐64 or IS6110 + 38 kDa + MPB‐64 As few as 2 colony‐forming units of M. tuberculosis cells, or as little as 15 fg of DNA, can be detected

67. PCR 100% sensitive and specific in multibacillary cutaneous tuberculosis DNA PCR positivity rates In paucibacillary tuberculosis 55% for tuberculosis verrucosa cutis 60% for lupus vulgaris The overall sensitivity - 73%

68. PCR Advantage The technique can be used in formalin fixed tissue sections Useful in paucibacillary lesions such as lupus vulgaris Disadvantage Tissue samples containing bacterial DNA may be positive because of bacteraemia Both false positive and false negative results can be obtained PCR is expensive and its use is not sustainable

69. Treatment Tuberculosis, pulmonary or extrapulmonary , is an AIDS‐defining illness HIV testing, with the patient’s consent Pulmonary, bone, lymph node or renal tuberculosis Combined approach with other specialists

70. DOT Directly observed therapy Ingestion of every drug dose is witnessed Risk assessment for adherence and DOT Homeless, Alcoholics or Drug abusers, Drifters , Seriously mentally ill patients, Patients with multiple drug resistances Patients with a previous history of non‐compliance

71. Treatment regimens The 6‐month four drug Regimen 6 months of treatment - 4 first line drugs For 2 months Combination of rifampicin , isoniazid , ethambutol and pyrazinamide Followed by a 4‐month Continuation phase of rifampicin and isoniazid

72. Treatment regimens Isoniazid - for the full 6 months 300 mg daily Rifampicin - for the full 6 months. 450 mg daily for those weighing ≤ 50 kg 600 mg daily for those ≥50 kg Pyrazinamide for the first 2 months 1.5 g daily for those weighing ≤ 50 kg 2.0 g daily for those ≥50 kg Ethambutol for the first 2 months 15 mg/kg body weight daily All the drugs are taken on an empty stomach once daily

73. Side effects

74. Isoniazid Efficacy, cheapness and low toxicity Peripheral neuropathy Most common in elderly Countered by pyridoxine 10 mg daily Hepatitis In adults over 35 years of age

75. Rifampacin Urine, sweat and tears may be coloured orange Elevated serum transaminases , during the first 2 months of treatment The induction of liver enzymes by rifampicin Reduce the effectiveness of oral contraceptives

76. Pyrazinamide Hepatitis in 1% Arthritis Precipitation of gout Cutaneous hypersensitivity in 3.5%.

77. Ethambutol Visual disturbances Retrobulbar neuritis Rare, reversible if detected early Stop the drug if visual symptoms develop. Visual acuity using a Snellen -before treatment Avoid drug in Young children Renal impairment

78. New antituberculosis drugs Bedaquiline Approved for use in the treatment MDR tuberculosis by the US FDA

79. HIV disease Currently the same 6‐ month regimen is recommended Treatment outcomes - worse

80. Multidrug‐resistant tuberculosis Defenition Resistance to rifampicin & isoniazid with or without resistance to other antituberculous drugs Loss of both The main bactericidal drug - isoniazid The main sterilizing drug – rifampicin The most important indicator of MDR tuberculosis? Rifampicin resistance

81. Xpert MTB/RIF Rapid molecular test Simultaneously test for pulmonary tuberculosis & rifampicin resistance WHO endorsed in 2010

82. Xpert MTB/RIF Disposable cartridge for the NAA examination Nucleic acid of the M.tuberculosis complex DNA is detected Semi -quantitative DNA-based real-time PCR

83. XDR tuberculosis Extensively drug‐resistant tuberculosis MDR strains with resistance to at least 3 of the main 6 classes of second line drugs Resistant to rifampicin , isoniazid , any fluoroquinolone and At least one of the injectable agents: capreomycin , kanamycin and amikacin 9.6% of MDR tuberculosis cases have XDR tuberculosis

84. Dermatological practice Standard 6‐month regimen Excision Small lesions of lupus vulgaris or warty tuberculosis Surgery Scrofuloderma Plastic surgery Disfigurement left by treated lupus vulgaris

85. Prognosis Early and accurate diagnosis Doubtful prognosis Tuberculosis has become generalized Tuberculosis has affected the meninges Mortality in patients with TB / HIV infection is higher Tuberculosis confined to the skin Responds well to multiple therapy Clinical response within 4–6 weeks Lupus vulgaris - faster response than scrofuloderma

86. Pregnancy ATT drugs contraindicated in pregnant women Streptomycin Kanamycin Amikacin Capreomycin Fluoroquinolones

87. Breastfeeding Concentrations of drugs in breast milk are too small to produce toxicity in the newborn Breastfeeding women taking INH should also take vitamin B6 supplementation RIF can cause orange discoloration of body fluids, including breast milk

88. Mycobacterium? Bacteria producing mould‐like pellicles when grown on liquid media Slender, non‐motile, aerobic, non‐ sporing rods A waxy coating that makes them resistant to most stains Once stained, however, they are not easily decoloured (acid‐fast)

89. Mycobacteria of dermatological interest Slow growers M. marinum M. kansasii M. avium M. intracellulare M. haemophilum M. ulcerans M. szulgai M. scrofulaceum M. tuberculosis Rapid growers M. abscessus (group) M. chelonae M. fortuitum (group) M. mageritense M. wolinskyi M. smegmatis M. mucogenicum Non‐ culturable M. leprae M. lepromatosis

90. Cell wall of the mycobacteria Responsible for their acid‐fast staining properties Peptidoglycan backbone of the cell abuts onto phospholipid plasma membrane Outside the peptidoglycan layer, and covalently bonded to it, there is a branched polymer arabinogalactan Onto this are attached the long chain fatty acids - mycolic acids Numerous other lipids and glycolipids are non‐covalently inserted into this lipophilic outer layer Lipoarabinomannan (LAM; a phosphatidylinositol mannoside ) is inserted into the plasma membrane Reaches out through the layers of the wall to the exterior

91. Outer lipids Mycolic acid cell wall skeleton Arabinogalactan Peptidoglycan Plasma membrane Lipoarabinomannan Phosphatidylinositol mannoside

92. HIV & M. tuberculosis co‐infection Latent M. tuberculosis infection The presence of viable bacilli in an individual without the symptoms and signs of disease One ‐third of the world’s population Immunosuppression caused by HIV infection increases risk of developing clinical disease HIV‐infected infants should not receive BCG vaccination

93. Non‐ tuberculous mycobacterial infections Found in the soil and water Municipal water sources M. kansasii , M. xenopi and M. simiae Animal to human or human to human transmission Risk of NTM infection HIV infection Iatrogenic immunosuppression - Anti-TNF Cosmetic procedures NTM infection is classified as WHO stage 4 of HIV infection

94. Immunology of tuberculosis After infection, only 5–10% of individuals develop progressive disease Bacteria remain viable in the tissues of subclinically infected individuals M. tuberculosis DNA Macrophages Fibroblasts Type II pneumocytes

95. Immunology of tuberculosis Reactivation and progressive disease Immunosuppressive drugs, HIV, Stress, Starvation.

96. Immunology of tuberculosis Koch phenomenon Robert Koch -late 19 th century Guinea pigs with tuberculosis would develop a severe necrotic reaction At the site of Injection of killed bacteria and Also in existing tuberculous lesions

97. Immunology of tuberculosis Immunocompetent individuals with tuberculosis Develop a necrotizing skin test response to M. tuberculosis antigens Account for much of the tissue damage associated with tuberculosis

98. Immunology of tuberculosis Persisters Biologically distinct from the bacteria that are associated with latency These are not eliminated by the drugs or by the immune response

99. Immunology of tuberculosis Failure of the immune response It does not quickly switch to the non‐necrotic protective mechanism As in BCG vaccinated individuals Treatment must continue for at least 6 months or relapse will occur

100. Tuberculin skin test Delayed ‐type hypersensitivity to mycobacterial antigens Following an intradermal injection of PPD Purified protein derivative A culture filtrate of tubercle bacilli Containing over 200 antigens shared with M. bovis BCG and many NTM Lack of specificity Major drawback in populations vaccinated with BCG

101. Tuberculin skin test Positive test Clinical or latent infection due to M. tuberculosis BCG vaccination Contact with environmental mycobacteria False negative reactions Severe illness, Active tuberculosis, HIV infection, Immunosuppressant drugs. Low sensitivity Immunosuppressed patients

102. Tuberculin skin test Mantoux method PPD (0.1 mL = 5 tuberculin units) Injected into the volar aspect of the forearm using a 27‐gauge needle to raise a small weal Diameter of the induration is measured after 48–72 h

103. Tuberculin skin test Cut ‐off of 5 mm induration Those at high risk of infection Close contacts of an active case Patients with radiographic abnormalities consistent with tuberculosis HIV infection Immunosuppressed with corticosteroids

104. Tuberculin skin test A cut‐off of 10 mm Migrants from endemic areas, homeless and residents of some urban areas Patients with diabetes, renal disease, silicosis Healthcare workers Other conditions associated with an increased risk of latent tuberculosis Cut ‐off of 15 mm Those with no risk factors

105. Tuberculin sensitivity Appears within a few weeks of infection with M. tuberculosis Usually lifelong Rarely tuberculin reactions may decrease in size (reversion) Small non‐necrotizing responses indicates? Protection Large necrotic responses ? Susceptibility or actual disease

106. Interferon‐ γ release assays For the diagnosis of latent tuberculosis T‐cell‐based blood tests Utilize antigens that are much more specific for M. tuberculosis than tuberculin Sensitivity is no better than that of the TST

107. Interferon‐ γ release assays Commercially available IGRAs QFT‐GIT - QuantiFERON ‐TB Gold In‐Tube test ( Qiagen , Valencia, CA, USA) T‐SPOT - TB test (T‐Spot) (Oxford Immunotec , Abingdon, UK) Both employ Early secretory protein 6 Culture filtrate protein 10 In addition the QFT‐GIT also uses TB7.7

108. Interferon‐ γ release assays These antigens are absent in most NTM and all strains of BCG, making these tests Useful in individuals who have received BCG vaccination

109. Interferon‐ γ release assays QFT‐GIT assay Uses an ELISA Measure the concentration of IFN‐γ in the plasma supernatant Following incubation of blood with the Antigens and Both negative and positive controls

110. Interferon‐ γ release assays The T spot assay Measures number of IFN‐γ‐producing T cells After overnight incubation in tissue culture plates.

111. UK National Institute for Health and Care Excellence (NICE) IGRAs should be considered Contacts with tuberculosis whose TST is positive In whom a TST would be less reliable IGRAs alone or in combination with a TST HIV‐positive individuals with CD4 counts of 200–500 cells/mm3 Other people who are immunosuppressed

112. British Thoracic Society Use TSTs and risk stratification for individuals being considered for anti‐TNF therapy Biological therapy for psoriasis

113. Diagnosis of mycobacterial infections Any obscure granulomatous or ulcerative lesion of the skin should be biopsied and cultured Visualize mycobacteria in specimens Light microscopy using Ziehl–Neelsen stain Fluorescence microscopy using auramine Not possible to distinguish between different species using microscopy

114. Mycobacterial culture Performed on solid or liquid media. Optimal culture temperature for NTM -30°C Optimal culture temperature of M. tuberculosisis 35°C 35°C often routinely used in laboratories for all mycobacterial cultures Yield of NTM by culture is affected

115. Mass spectrometry Reported to be a rapid technique for mycobacterial identification Urinary lipoarabinomannan as a diagnostic test for tuberculosis is being studied

116. Ziehl neelsen stain procedure

117. Acid-Fast Staining Instructions  Air dry and heat fix a thin film of microorganisms. Allow the slide to cool Flood the slide with  Carbolfuchsin . Steam the slide with a Bunsen burner over the sink. Let the slide set for 5 minutes.  Rinse with water . Flood slide with Acid Alcohol for 30 seconds. Rinse with water .

118. Acid-Fast Staining Instructions  Counterstain by flooding the slide with  Methylene Blue for 30 seconds. Rinse with water Dry the slide by putting it between the pages of a book of Bibulous paper . View organisms using the oil immersion objective of your microscope

119. Primary inoculation tuberculosis

120. Primary inoculation tuberculosis Tuberculous chancre Tuberculosis primary complex Inoculation of M. tuberculosis into the skin Individual without natural or artificially acquired immunity to this organism The initial lesion contains many organisms ( multibacillary )

121. Primary inoculation tuberculosis Some form of injury is mandatory Abrasions and minor injuries Operations Tattooing Mouth ‐to‐mouth artificial respiration Acupuncture Sexual transmission

122. Primary inoculation tuberculosis Commonly affects children Esp.who have not received BCG vaccination Who are exposed to pulmonary tuberculosis Lupus vulgaris may develop at the site of inoculation Other reported Warty tuberculosis Scrofuloderma Systemic tuberculosis

123. Pathology Early changes Acute neutrophilic inflammation Necrosis in both skin and affected lymph nodes Numerous bacilli are present After 3 - 6 weeks The infiltrate becomes more granulomatous Caseation appears, coinciding with the disappearance of the bacilli

124. Primary inoculation tuberculosis Presentation? Painless, non‐healing ulcer or lesion with localized lymphadenopathy , esp. in a child

125. Primary inoculation tuberculosis Incubation - 2–4 weeks Brownish papule, nodule Ulcer Undermined edge Granular haemorrhagic base In time The edge becomes firmer Adherent crust develops

126. Primary inoculation tuberculosis When obvious trauma is absent Initial lesion is often small with a central silvery scale May show ‘apple jelly’ nodules on diascopy Sites - face, hands and lower extremities Apparent healing conceal Active infection below the surface & Development of a cold abscess. Regional lymphadenopathy - after 4–8 weeks Occasionally Lupoid nodules occur around the healed ulcer or Deeper infection simulates scrofuloderma

127. Cutaneous equivalent of the Ghon focus in the lung? The complex of the tuberculous chancre and regional lymphadenopathy

128. Clinical variants Conjunctival lesions may cause oedema and irritation Ulceration and oedema of the lids, with preauricular lymphadenitis Oral lesions Uncommon Painless lesions may form in a tooth socket or on the gums simulating gingivitis. Oral lesions may be an expression of oral primary tuberculosis

129. Differential diagnosis Other causes of ulceration Other mycobacteria (e.g. M. marinum ), Buruli ulcers, actinomycosis , Cutaneous leishmaniasis , Malignancies.

130. Disease course & prognosis Heal slowly over many months Lupus vulg /TBVC may develop at the site of original lesion. Haematogenous spread Development of tuberculosis elsewhere Miliary tuberculosis Erythema nodosum The enlarged draining lymph nodes Often - Subside slowly, calcifying Less often, cold abscesses and sinuses develop producing scrofuloderma

131. Investigations Acid‐fast bacilli are seen in The primary skin lesion and in draining nodes in the early stages Tuberculin test is usually negative at the beginning of the course

132. Scrofuloderma Tuberculosis colliquativa cutis The commonest form of cutaneous tuberculosis in childhood Direct invasion of the tubercle bacillus into the skin from an underlying contiguous tuberculous focus Mycobacterium tuberculosis.

133. Underlying tuberculous focus Lymph gland, an infected bone or joint, lacrimal gland or duct, breast or testes Cervical, epitrochlear and retroauricular gland Axillary lymph nodes Osteomyelitis of the scalp, ribs or limbs

134. Histopathology Ulcerated dermal abscess with an ill‐defined histiocytic component Marked caseation necrosis containing numerous bacteria, in the deep structures

135. Asymptomatic swelling or ulcer or discharging sinus Extensive ulcerative lesions, particularly on the scalp, may give rise to diagnostic difficulties

136. Presentation Asymptomatic, bluish red, subcutaneous swellings that for several months and overlie an infected gland or joint. They break down to form undermined ulceration with granulating tissue at the base. Numerous fistulae may intercommunicate beneath ridges of a bluish skin. Progression and scarring produce irregular adherent masses, densely fibrous in places and fluctuant or discharging in others. Excessive granulation tissue may give rise to fungating tumours . After healing, characteristic puckered scarring or cord‐like scars.

137. Differential diagnosis Non tuberculous mycobacterial infection especially M. avium complex lymphadenitis M.scrofulaceum - more benign Sporotrichosis , Actinomycosis , Syphilitic gummata , Hidradenitis suppurativa , Melioidosis , Bacterial abscess .

138. Investigations Skin biopsy should be taken from the edge of the sinus or ulcer. Tubercle bacilli can usually be easily identified on biopsy specimens or cytology smears from fine‐needle aspirations Mycobacterial culture Mantoux test is normally positive. HIV infection and other causes of immunosuppression need to be excluded

139. Orificial tuberculosis Tuberculosis cutis orificialis Painful ulcerated lesions due to tuberculous infection of the mucosa or the skin adjoining orifices. The patient will usually have advanced internal tuberculosis. The most commonly affected area is the oral mucosa, especially the tongue Middle ‐aged and elderly males

140. Rare multibacillary form Advanced pulmonary, intestinal or genito ‐urinary disease Buccal mucosa and around the anus, vulva or penis Autoinoculation of organisms into a break in the mucosal surface

141. Oral lesions Ingestion of bacilli in sputum haematogenous spread or direct spread from adjacent organs Perianal lesions Reported without pulmonary or gastrointestinal involvement

142. Pathology Variable Nonspecific inflammatory type. In most cases a tuberculoid infiltrate with pronounced necrosis is found in the deep dermis. Tubercle bacilli are usually easy to demonstrate

143. History Painful ulceration around orifices and Constitutional symptoms fever, malaise, weight loss and night sweats. Presentation Severely ill adult with Advanced visceral tuberculosis Impaired cell‐mediated immunity

144. Small, red, oedematous nodules rapidly break down to form painful, shallow ulcers with undermined bluish edges. The ulcers seldom exceed 2 cm No tendency to heal spontaneously Tongue, particularly tip and lateral margins Granulomatous swelling of the lips Gingival involvement

145. Perianal area ulcers may be sharply demarcated with erythematous borders and a purulent base Vulval lesions have a similar appearance and are often very painful

146. Clinical variants Plaques similar to lupus vulgaris or a hypertrophic lesion similar to tuberculosis verrucosa cutis

147. Differential diagnosis Oral lesions Crohn disease, Mucocutaneous leishmaniasis , Oral paracoccidiomycosis and rhinoscleroma . Ano ‐genital lesions Malignancy, Nicorandil ‐induced ulceration, Crohn disease, Cutaneous amoebiasis , Anal paracoccidiomycosis , Chronic herpes simplex infection Syphilis

148. Disease course Will not heal spontaneously and can be Slow to respond to antituberculous treatment and prognosis Exclude associated systemic tuberculosis

149. Investigations Multiple acid‐fast bacilli Histology from a skin biopsy sample occasionally smear cytology from the base of a purulent ulcer Cultures of tissue are normally positive within 6 days. If available PCR may give a result within 24 h Tuberculin test is often negative

150. Acute cutaneous miliary tuberculosis Tuberculosis cutis miliaris disseminata Tuberculosis cutis miliaris acuta generalisata Rare Usually seen in advanced pulmonary or meningeal and disseminated tuberculosis. It affects infants and young children or immunosuppressed patients

151. Pathology Necrotizing tuberculous granulomas with multiple acid‐fast bacilli. Presentation Crops of minute bluish papules, vesicles, pustules or haemorrhagic lesions in a patient who is obviously ill Prognosis Poor, but response to treatment is possible

152. All over the body Most frequently Trunk, thighs, buttocks and genitalia The vesicles may become necrotic to form small ulcers Neonates born to tuberculous mothers Milder form Limited visceral involvement Few scattered papule

153. Investigations Tuberculin test is negative

154. Metastatic tuberculous abscess

155. Metastatic tuberculous abscess Tuberculous gumma Disseminated haematogenous spread of mycobacteria Single or multiple dermal subcutaneous nodules May become fluctuant or break down to form ulcers

156. Haematogenous dissemination during periods of lowered resistance Malnourished children Immunodeficient adults Noted after venepuncture

157. Pathology Massive necrosis with copious amounts of bacteria. Investigations Culture Screen for an underlying focus of tuberculosis and causes of immunosupression . The tuberculin test is usually positive

158. Presentation Firm, subcutaneous nodule or as a non‐tender, fluctuant abscess Extremities are more often affected than the trunk. The overlying skin may break down to form an undermined ulcer, often with sinuses or fistulous tracts Lesions may be multiple Lesions may cause carpal tunnel syndrome

159. Differential diagnosis Pyogenic bacterial infections, Syphilis, Non ‐ tuberculous mycobacterial infections, Pyoderma gangrenosum Some fungal infections

160. Tuberculids

161. Cutaneous hypersensitivity reactions to haematogenous dissemination of M. tuberculosis or its antigens from a primary source in an individual with strong antituberculous cell‐mediated immunity.

162. Diagnostic criteria Tuberculoid histology on skin biopsy, a strongly positive Mantoux reaction, the absence of M. tuberculosis in the smear Negative culture Resolution of the skin lesions with antituberculous therapy

163. Classification Micropapular : lichen scrofulosorum . Papular : papulonecrotic tuberculid . Nodular: erythema induratum of Bazin or nodular tuberculid . M. tuberculosis DNA by PCR

164. Erythema induratum of Bazin Nodular vasculitis Multifactorial disorder with many different causes Tuberculosis being one of them

165. Lichen scrofulosorum has been noted to occur after the initiation of antituberculous treatment Probably represents a shift in the cell‐mediated immune status of the patients

166. Lichen scrofulosorum Tuberculosis cutis lichenoides Tuberculid first described by Hebra in 1868. Lichenoid eruption of minute papules predominantly in children and adolescents with active tuberculosis Strongly positive tuberculin reaction. Often measuring 18 mm or larger The site may ulcerate

167. Asymptomatic , tiny, follicular papules Skin coloured to erythematous Closely resemble lichen nitidus Cutaneous marker for underlying tuberculosis and up to 73% Cervical, hilar and mediastinal lymph nodes (up to 65%). Other foci include the lung, bone or intracranial sites

168. Causative organisms Mycobacterium tuberculosis. Mycobacterium bovis . Mycobacterium avium . Mycobacterium szulgai . BCG vaccination

169. Other forms of cutaneous tuberculosis, may coexist Lupus vulgaris , tuberculous gumma , papulonecrotic tuberculid Tuberculosis verrucosa cutis,

170. Pathophysiology Type III hypersensitivity reaction to a haematogenous spread of mycobacteria occur in persons with a high sensitivity to tuberculin Continued formation of antigen–antibody complexes may lead to a type IV hypersensitivity reaction and granuloma formation Up ‐regulation of their immune system AIDS after ART and antibacterial treatment

171. Pathology Superficial dermal granulomas Surround hair follicles and sweat ducts May occupy several dermal papillae. Epithelioid cells, lymphocytes and occasional giant cells are seen. Usually there is no caseation . Mycobacteria Not seen in the sections Cannot be cultured from biopsy material. Mycobacterial DNA may be detected by PCR

172. History Skin lesions are usually subtle and asymptomatic Symptoms related to an underlying focus of tuberculosis elsewhere, such as lymphadenopathy

173. Symptomless, 0.5–3.0 mm diameter, closely grouped, lichenoid papules. The lesions are usually skin coloured May be yellowish or reddish brown. Often perifollicular Can appear in groups or in an annular arrangement or coalesce into confluent plaques The papules may have an adherent crust or small pustule

174. Mainly found on the abdomen, chest, back and proximal limbs May occur on the face,palms and soles, vulva Clinical variants Lichenoid Psoriasisform Granuloma annulare ‐like

175. Differential diagnosis Lichen nitidus lesions are more shiny and tend to be peripheral; Keratosis spinulosa lesions have spiny projections over lichenoid papules; Keratosis pilaris , Lesions are non‐inflammatory - upper thighs and arms; Papular or lichenoid sarcoidosis , Secondary syphilis and Drug eruptions. Pityriasis rosea - Annular lesions - resemble

176. lesions usually clear within 4 weeks and sometimes as early as 2 weeks,without scarring.

177. Papulonecrotic tuberculid

178. Papulonecrotic tuberculid Tuberculosis papulonecrotica Children and young adults. Asymptomatic, symmetric, clusters of small, inflammatory, erythematous papules May become pustular or necrotic Evolve into discrete crusted ulcers which heal over weeks with varioliform scarring Perniotic areas ? Ears , acral limbs and extensor surfaces of the joints

179. Pernio Also referred to as chilblains Two Old English words "chill" ( cold ) " blegen " (sore) Affects acral skin Macules , papules, or nodules - in response to exposure to cold, damp environments Secondary pernio Associations with other conditions - SLE

180. May occur on the lower abdomen, trunk, buttocks and scalp Localized forms Rare and mainly involve the genitalia May evolve into lupus vulgaris Tuberculin test is normally positive Severe & even necrotic reactionwithin 8–12 h

181. Pathology Subacute lymphohistiocytic vasculitis that causes thrombosis and destruction of small dermal vessels Lead to a wedge‐shaped infarct‐like lesion with a large central zone of coagulation necrosis Surrounded by inflammation extending from the superficial to the deep dermis, and sometimes into the subcutaneous tissues.

182. Histiocytic palisade, similar to GA, is seen around larger lesions. The involvement of adjacent small vessels Mild lymphocytic vasculitis to fibrinoid necrosis and thrombotic occlusion

183. Causative organisms M. tuberculosis M. kansassi M. avium complex M. bovis

184. Presentation Recurring crops of symmetrical, hard, dusky red papules. Legs , knees, elbows, hands and feet - Perniotic areas Crust or ulcerate, leaving pigmented, sometimes atrophic, varioliform scars over a few weeks New crops may continue over months or years. In some cases, showers of rapidly healing lesions occur In others a chronic open ulcer may last for some months In children - Phlyctenular conjunctivitis

185. Clinical variants Isolated lesions on the genitalia, particularly the penis Verrucous variant mimicking Kyrle disease

186. Differential diagnosis Pityriasis lichenoides , lesions may be more widespread affect the palms and soles; Leukocytoclastic vasculitis Lesions are more pleomorphic ; Nodular prurigo

187. With treatment - clear as early as 3–4 weeks Investigations Lesional biopsy Tuberculin test is usually strongly positive PCR is frequently positive IFN‐ γ release assay – if PCR negative Therapeutic trial of specific antituberculous therapy

188. Erythema induratum of Bazin

189. Erythema induratum of Bazin Nodular vasculitis Without evidence of associated tuberculosis Bazin disease Tuberculosis cutis indurativa The most commonly reported form of tuberculid Crops of small, tender and painful erythematous or dusky nodules or deep‐seated plaques which may ulcerate On the calves. Most patents tuwill have a positive berculin test or IGRA

190. Nodular vasculitis Chronic hepatitis C M. chelonae Predisposing factors Past or active foci of tuberculosis PPD specific T cells capable of producing IFN‐γ Formation of erythema induratum as a type of delayed hypersensitivity response Immune complex deposition may play a role in the vasculitic component

191. Pathology Focal or diffuse, lobular or septolobular , granulomatous panniculitis Neutrophilic vasculitis of either large or small blood vessels Areas of coagulative and caseation necrosis Poorly developed, granulomas - common Mixed , pallisading and lipophilic granulomas Mycobacterial DNA can be found in up to 77%

192. History Generally asymptomatic Acute nodules can be painful. Symptoms of associated tuberculosis elsewhere, for example lymphadenopathy

193. Presentation Indolent eruption of ill‐defined nodules or subcutaneous plaques Usually affecting the posterior aspect of the lower legs of young or middle‐aged women Other body areas, such as the upper limbs, thighs, buttocks and trunk The plaques are usually indurated with a scaly surface Follicular perniosis may be present

194. The plaques are usually indurated with a scaly surface Follicular perniosis may be present Lesions may ulcerate, usually centrally may be precipitated by cold weather or venous stasis Ulcers Ragged, irregular and shallow, with a bluish edge. The lesions heal with atrophic, hyperpigmented scarring

195. Clinical variants Nodular tuberculid Pathology is at the junction of the dermis and subcutaneous fat Nodular granulomatous phlebitis Superficial thrombophlebitic tuberculid Non ulcerating subcutaneous nodules Distributed along the course of the great saphenous vein

196. Differential diagnosis Erythema nodosum , Pancreatic panniculitis , Polyarteritis nodosa , Lupus profundus , Subcutaneous sarcoid , cutaneous T‐cell lymphoma, Perniosis - chilblains

197. Disease course and prognosis Chronic Recurrent crops of new lesions sometimes over many years. Response to antituberculous therapy may take between 1 and 6 months Resolution may be slow, even with adequate therapy

198. Investigations Clinical morphology Positive tuberculin test Circumstantial evidence of tuberculosis elsewhere Histopathological findings M. tuberculosis DNA by PCR on the skin biopsy IGRAs such as the QuantiFERON ‐TB Gold test, diagnosis of latent tuberculosis Good response to antituberculous therapy Testing for chronic hepatitis C viral infection and other infections

199. Mx ATT Resting Non ‐steroidal antiinflammatory drugs Compression bandaging

200. Other nodular tuberculids Erythema nodosum Nodular vasculitis – DD - erythema induratum Lesions do not usually ulcerate Lupus miliaris disseminatus faciei DD - rosacea Tuberculous mastitis

201. Tuberculous mastitis One of the causes of granulomatous mastitis Clinically and radiologically indistinguishable from breast cancer. The disease is most often Ulcerative plaques, nodules, abscesses and occasionally sinuses on the breast Female - usually in their twenties

202. On histology, often performed on specimens from fine‐needle aspiration, Granulomas are seen with fat necrosis Acid ‐fast bacilli are rarely found. The tuberculin test is normally positive PCR is sometimes positive

203. Non ‐ tuberculous mycobacteria Disease‐causing mycobacteria other than those of the M. tuberculosis complex M. tuberculosis, M. bovis, M. Bovis,BCG, M. leprae