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Dermatological manifestations of tuberculosis in adults and children
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Dermatological manifestations of tuberculosis in adults and children H Francois Jordaan and Johann W Schneider
INTRODUCTION The late eighteenth and early nineteenth centuries are known as the Age of Reason and the era of the establishment of dermatology as a specialty. At that time, Willan and Bateman set forth accurate descriptions of the basic types of skin lesions. Initially skin lesions were grouped into ‘orders’ and ‘genera’. Skin lesions of TB appeared in the order of ‘tubercles’ and in the genus of ‘lupus’. With the Age of Reason came the Industrial Revolution and the three key factors that lead to a rapid increase in the incidence of TB, namely urban congestion, poverty, and a susceptible population. By the midnineteenth century, TB killed about one-quarter of young adults in industrialized countries. The high death rate from birth to the age of 6 or 7 years was due to bovine TB transmitted by raw milk. The second peak in the death rate was between the ages of 25 and 50 years. This was due to human tubercle bacilli transmitted largely by droplet infection. Also by this time, dermatologists had begun to differentiate between localized cutaneous TB and skin manifestations of systemic TB, and to classify skin lesions of TB based on their morphology. Worcester classified TB lesions involving both the skin and deeper tissues as ‘lupus exedens’ and TB confined to the skin as ‘lupus non-exedens’. In 1876 Neligan described cases with localized skin lesions as ‘lupus superficialis’ and ‘lupus serpiginosus’ and cases with skin lesions and ‘scrofula’ (TB of lymph nodes) associated with TB of deeper tissues as ‘lupus devorans’. Fox and Duhring referred to TB of the skin simply as ‘lupus vulgaris’. Robert Koch reported on his bacteriological findings of TB in 1882. He stained and cultured tubercle bacilli and reported the transfer of TB to animals with these cultures. Koch’s postulates provide the key method for identifying the causative agent of all forms of TB of the skin.1 In 1903, Niels Ryberg Finsen was awarded the Nobel Prize for his invention of light therapy for cutaneous TB (lupus vulgaris). It was recently demonstrated that Mycobacterium tuberculosis produces coproporphyrin III. Radiation with light of 400 nm led to the production of singlet oxygen.2 Since these early days, various classifications have been proposed for cutaneous TB. However, it was the classification of Beyt et al.3 and minor modifications of this classification that gained general approval. The global expansion of TB during the past decade confirms that TB is a growing health problem, especially in populations with a high prevalence of human immunodeficiency virus (HIV) infection.4 The acquired immunodeficiency syndrome (AIDS) pandemic and increased number of immunocompromised patients
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contribute significantly to the increased incidence of TB and its cutaneous manifestations.5,6 Many recent publications emphasize this phenomenon and highlight the importance of cutaneous manifestations of TB as an important clinical and diagnostic challenge.6,7 Cutaneous TB can mimic the clinicopathological features of many other skin diseases, and underlying systemic or organ TB can be notoriously difficult to detect, resulting in considerable diagnostic challenges and pitfalls and potential delays in diagnosis and institution of treatment.8,9 Patient immunity to M. tuberculosis, previous infection, and the route of infection determine the clinicopathological features of cutaneous TB in a particular patient. Systemic TB is present in the overwhelming majority of patients, and direct cutaneous or mucosal inoculation with M. tuberculosis is rare.6,10 Cutaneous manifestations of TB include a wide and often overlapping spectrum of papules, pustules, papulonecrotic and papulopustular lesions, nodules, panniculitis, plaques, verrucous lesions, ulcers, chronic sinuses, and scars.11
CLASSIFICATION OF CUTANEOUS TUBERCULOSIS Over the years, a number of classifications of cutaneous TB have been proposed. Accurate classification of the varied expressions of cutaneous TB is relevant in order to improve diagnostic accuracy and appropriate prognostication and treatment of patients.11 The classification of Beyt et al.3 gained general acceptance, and a modification of this classification has been utilized in the latest edition of Rook’s Textbook of Dermatology.12 More recent modifications of the classification adhere to the route of infection, but acknowledge the expanding spectrum of cutaneous TB and include tuberculids as a variant of cutaneous TB rather than a cutaneous hypersensitivity reaction to underlying systemic or organ TB (Table 47.1).13 Complications of Bacillus Calmette–Gue´rin (BCG) vaccination include disseminated infection with spread to the skin,14,15 scrofuloderma,16 papular tuberculids,17 erythema induratum,18 lupus vulgaris,19 lichen scrofulosorum,20 and keloids,11 and should therefore be included in a classification of cutaneous TB (Table 47.1). Considerable clinicopathological overlap and non-specific clinical features complicate the traditional classification of cutaneous TB.3 Overlapping clinicopathological features emphasize that the traditional subtypes of cutaneous TB represent a spectrum with variable and overlapping combinations of clinical and histopathological features, variable success for detecting tuberculous bacilli in skin lesions, and variable demonstration of underlying
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Dermatological manifestations of tuberculosis in adults and children
Table 47.1 Classification of cutaneous tuberculosis Inoculation tuberculosis from exogenous source (primary cutaneous tuberculosis)
Primary tuberculous chancre Verrucosa cutis (warty TB) Some cases of lupus vulgaris-type TB
Table 47.2 A practical guide to the diagnosis and management of cutaneous tuberculosis Definite cutaneous TB Clinical morphology
Secondary tuberculosis from endogenous source
Direct spread to the skin (scrofuloderma-type TB) Autoinoculation (orificial TB)
Histopathology
Haematogenous tuberculosis
Miliary TB Some cases of lupus vulgaris-type TB Tuberculous gumma
Tuberculid-type tuberculosis (tuberculids or eruptive tuberculosis)
Papulonecrotic-type TB Erythema induratum of Bazin/nodular vasculitis-type TB Lichen scrofulosorum-type TB Nodular tuberculid
ZN and/or culture and/or PCR on skin lesion biopsy ZN and/or culture and/or PCR on specimen from origin other than skin Mantoux test result
Phlebitic tuberculid-type TB BCG-related TB
non-cutaneous TB. The clinical management of patients will depend on the level of certainty of the diagnosis of TB rather than the subtype of cutaneous TB. A more useful approach to cutaneous TB from a clinical perspective should combine clinicopathological findings and the results of special investigations to offer practical guidelines and stratification of patients as definitive, probable, and possible cutaneous TB, respectively (Table 47.2).
PATHOGENESIS AND MORPHOLOGY The genus Mycobacterium contains more than 80 species, most of which are harmless environmental saprophytes. The most important obligate human pathogens are M. tuberculosis and Mycobacterium leprae, but others such as Mycobacterium avium and Mycobacterium ulcerans are also significant. These are now best referred to as environmental mycobacteria, also referred to as non-tuberculous mycobacteria (NTM). Cutaneous involvement by M. tuberculosis can follow direct inoculation of organisms from an exogenous source; direct spread of organisms from an endogenous source such as tuberculous lymphadenitis extending to the skin (scrofuloderma) or autoinoculation, e.g. mucocutaneous involvement from pulmonary TB (orificial TB); haematogenous dissemination of organisms from a distant site; or haematogenous spread of mycobacterial components including DNA as seen in the so-called tuberculids.21,22 These various pathogenic mechanisms are further modulated by the number and the virulence of the organisms and the concerned host’s level of immune competence and genetic predisposition to infection. These complex interactions between host
Radiograph findings compatible with TB, e.g. lung, bone Response to anti-TB treatment
Probable cutaneous TB
Possible cutaneous TB
Variable combinations and transitions of papular, nodular, pustular, papulonecrotic, pustulonecrotic, ulcerative, vegetating skin lesions Variable combinations and transitions of granulomatous inflammation, mixed acute and chronic inflammatory cells, necrosis, vasculitis, organization and fibrosis, other non-specific changes – – +a
NEFD
+b
–
NEFD
–
NEFD
+b (only in children <5 years old) +b
NEFD
NEFD
EFD
Other
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–
ZN, Ziehl–Neelsen stain; PCR, polymerase chain reaction; NEFD, not essential for diagnosis; EFD, essential for diagnosis (but not necessarily proof of TB). a When only ZN positive, distinction from environmental (nontuberculous) mycobacteria is necessary by culture and/or PCR. b Any positive establishes the diagnosis of probable TB.
factors on the one hand and the organism and other environmental factors on the other hand result in the wide spectrum of clinicopathological manifestations of cutaneous TB.23 The microscopic hallmark of cutaneous TB is granulomatous inflammation, which may vary from sarcoidal or tuberculoid granulomas to necrotizing, suppurative, or palisading granulomas. Combinations of various patterns of granulomatous inflammation are common. In some cases of erythema induratum of Bazin and papulonecrotic tuberculid, necrotizing vasculitis is present.24,25 The epidermis may be atrophic, hyperplastic, or ulcerated. Lymphocytes, macrophages, plasma cells, and sometimes neutrophils and eosinophils constitute the inflammatory cell population involved. Scarring may be mild, moderate, or marked. Although the histopathological findings are often quite characteristic, they are not diagnostic per se and a specific diagnosis depends on clinicopathological correlation and the demonstration of M. tuberculosis organisms in skin lesions or other organs. The detection of M. tuberculosis organisms in skin lesions depends largely on the type of cutaneous involvement and the adequacy of the diagnostic sample tissue. Organisms are usually easy to detect in skin lesions associated with miliary TB or scrofuloderma, difficult to find in specimens obtained from lupus vulgaris lesions, and absent in tuberculids where demonstration of M. tuberculosis DNA by polymerase chain reaction (PCR) is required.26–29
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The variable and overlapping clinical and pathological features of cutaneous TB often defy the various types of clinical lesions depicted in traditional classification, leading to diagnostic challenges. Despite these limitations, an understanding of the pathogenesis and various morphological patterns of cutaneous TB facilitates the recognition of the various clinical manifestations of the disease (Table 47.1).
PRIMARY CUTANEOUS TUBERCULOSIS Primary cutaneous TB follows the direct inoculation of M. tuberculosis organisms into the skin due to penetrating trauma such as ear piercing, circumcision, tattooing, or injury to laboratory staff.30 The subsequent indurated papulonodular lesion appears within 1–3 weeks and tends to ulcerate, resulting in a primary chancre and regional lymphadenopathy, similar to the pulmonary Ghon complex. A similar picture can follow BCG vaccination.21 Biopsies from a primary chancre reveal mixed acute and chronic inflammation that leads to necrosis, ulceration, and granulomatous inflammation after a
few weeks.31 Organisms are easily demonstrated in tissue sections by Ziehl–Neelsen stain. Underlying systemic TB is absent. Inoculation of M. tuberculosis bacteria into the skin of patients with strong immunity may lead to TB verrucosa cutis.32 This unusual expression of cutaneous TB is characterized initially by a warty indurated nodule that expands in time to form a verrucous plaque. The skin lesions typically involve the dorsum of the hand or fingers following exposure to infected tissues or sputum. Pathological findings include epidermal hyperplasia, hyperkeratosis, papillomatosis, and mixed acute and chronic inflammation with caseating granulomas in the dermis. Ziehl–Neelsen stain of tissue sections will usually show sparse bacilli. Lupus vulgaris can follow inoculation of organisms into the skin of patients with previous or current TB, but, more often, it follows haematogenous or lymphatic dissemination to the skin from underlying and often subclinical TB. Less commonly it may develop at the site of BCG inoculation.33 The skin lesions are characterized by coalescing papules that form a plaque that has traditionally been described as resembling apple jelly nodules on diascopy (Fig. 47.1).
Fig. 47.1 Cutaneous TB, lupus vulgaris variant involving the tip of the nose (A) and the nose and upper lip (B). The nose is a characteristic site of involvement. The differential diagnosis in (B) should include discoid lupus erythematosus. Plaques are often a typical clinical manifestation of lupus vulgaris as demonstrated in this lesion involving the arm and showing an expanding nodular border with central atrophic scarring (C). Note the central atrophy and scarring in this example of lupus vulgaris involving the lateral neck (D).
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Other clinical manifestations include warty plaques, ulceration, cellulitis, and rarely alopecia.34 Although the head and neck and especially the nose are typically involved, lupus vulgaris may less commonly involve the limbs and feet, gluteal area, trunk,35 and penis.36 Disseminated lesions may also occur. Lupus vulgaris is a chronic condition, and it is often characterized by considerable delay in arriving at the correct diagnosis.37 Subsequent scar formation is therefore not uncommon. Squamous cell carcinoma and less commonly basal cell carcinoma, melanoma, and lymphoma may complicate long-standing lupus vulgaris.38,39 Histopathological features include intradermal tuberculoid granulomas with little or no necrosis, mimicking sarcoidosis.40 Pseudoepitheliomatous hyperplasia of the epidermis may simulate squamous cell carcinoma, especially in superficial biopsies. Less frequently, epidermal atrophy and ulceration may be present. Organisms are usually rare and difficult to find in Ziehl–Neelsen-stained sections.
SECONDARY TUBERCULOSIS FROM ENDOGENOUS SOURCE Orificial tuberculosis is characterized by ulceration at mucocutaneous orifices including the mouth, nose, perianal region, and genitalia (Fig. 47.2).41 The clinical lesions follow autoinoculation of the mucocutaneous surface from underlying active TB with abundant organisms. Patients present with persistent and undermined painful ulcers. Biopsies of the ulcers typically show prominent necrosis with
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Fig. 47.2 Orificial TB with involvement of the tongue.
mixed acute and chronic inflammation and inconspicuous granulomas. Ziehl–Neelsen-stained sections reveal abundant organisms. Scrofuloderma represents direct spread to the skin from underlying tuberculous infection such as tuberculous lymphadenitis, arthritis, or osteomyelitis.42,43 Typical lesions include ulcerating nodules, ulcers, draining sinuses, and scarring (Fig. 47.3). Frequently involved sites include the neck and submandibular regions, but many sites could be involved, depending on the location of the focus of TB. Active TB is present and histological findings typically
Fig. 47.3 Cutaneous TB, scrofuloderma variant. Note the extensive ulceration and draining sinuses in the inguinal region (A) and the underlying lymphadenopathy and linear arrangement ulceration on the lateral side of the neck (B) and the superficial scarring (C). The linear arrangement corresponds to the lymphatic drainage in this area.
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demonstrate ulceration, caseating granulomas, abscess formation, and variable number of acid-fast bacilli.
HAEMATOGENOUS TUBERCULOSIS Miliary TB has a poor prognosis if not diagnosed and treated timeously and usually occurs in infants and children and follows haematogenous dissemination of numerous M. tuberculosis organisms from underlying active TB usually in the lung. Typical skin lesions include papules, pustules, vesiculopustular lesions, small ulcers, haemorrhagic lesions, and subcutaneous abcesses.44 Miliary TB may occur in immunocompromised patients, including patients with AIDS.45 Lesions that simulate folliculitis may cause diagnostic problems.46 A high index of suspicion is important to establish a diagnosis. Histopathological features include necrosis, small dermal abscesses, and leucocytoclastic vasculitis, often without granulomatous inflammation.45 Since underlying TB is often not suspected clinically, the histopathological features could be interpreted as non-specific. However, Ziehl–Neelsen stain of tissue sections will usually show numerous acid-fast bacilli. Tuberculous gumma (metastatic tuberculous abscess) follows haematogenous dissemination of organisms from a tuberculous focus elsewhere in the body to the subcutaneous tissue with subsequent development of a subcutaneous abscess.47 Patients with malnutrition and compromised immunity are more frequently affected.48 The clinical features include one or more subcutaneous nodules that may soften because of necrosis. Subsequent chronic ulceration may simulate scrofuloderma. Biopsies from affected sites reveal granulomatous inflammation, often with extensive caseous necrosis, that involves primarily the subcutaneous tissue with extension to the dermis. Ziehl–Neelsen stain typically shows sparse bacilli.
TUBERCULIDS Tuberculids include a spectrum of related and often overlapping clinicopathological manifestations of cutaneous TB that occur in patients with tuberculin hypersensitivity and with underlying and often subclinical tuberculous infection elsewhere in the body.12,29 Mycobacterium tuberculosis organisms are absent in the skin lesions when assessed by Ziehl–Neelsen stains and culture, but M. tuberculosis DNA can be demonstrated by PCR in 25–50% of cases.28,29,49,50 A good clinical response of the skin lesions to anti-TB treatment provides further evidence that the tuberculids are best regarded as a variant of cutaneous TB rather than an immunological reaction to TB elsewhere in the body, including BCG.12,29,51 Clinicopathological variants of tuberculid-type cutaneous TB include papulonecrotic tuberculid (PNT), erythema induratum of Bazin (EIB), lichen scrofulosorum, nodular tuberculid, and nodular granulomatous phlebitis. Concurrent lesions of different expressions of tuberculid-type TB overlapping histopathological features suggest that these clinicopathological variants form part of a single spectrum of disease.12,52 PNT is characterized by recurring crops of skin-coloured or red papules that can show central necrosis, ulceration, crusts, and pustules that heal in time with small depressed scars (Fig. 47.4A–D). The skin lesions can occur in children and in adults and they typically involve the ears and extensor surfaces of the limbs around the elbows and knees.12,21,27 The lesions may be symmetrical and widespread or localized to specific areas such as the penis.53 Occasionally a Koebner phenomenon may occur (Fig. 47.4E). Confluence and
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ulceration of the lesions may occur in patients with AIDS (Fig. 47.4F). PNT may follow BCG vaccination.54 Histopathological features include wedge-shaped necrosis of the upper dermis with the base towards the epidermis which frequently shows ulceration.27,55,56 The area of necrosis is often folliculocentric and flanked by granulomatous inflammation and chronic inflammatory cells (Fig. 47.4).55 Leucocytoclastic vasculitis may be present.24 Ziehl– Neelsen stain for acid-fast bacilli is always negative. Erythema induratum of Bazin or erythema induratum/nodular vasculitis is a form of panniculitis characterized by red violaceous nodules that classically occur on the calves of women especially in winter (Fig. 47.5A and B).57 The nodules may be painful and undergo ulceration that tends to be chronic and to heal with scarring. Biopsies from EIB skin lesions reveal variable features of septolobular panniculitis, necrosis, granulomatous inflammation, and vasculitis of smaller or larger blood vessels (Fig. 47.5C and D).25,57 Acid-fast bacilli are invariably absent. Lichen scrofulosorum typically affects paediatric patients and young adults and is often associated with localized tuberculous lymphadenitis or organ TB, particularly tuberculous osteomyelitis. The condition is characterized by asymptomatic yellowish papules on the trunk (Fig. 47.6).51,58 The skin lesions tend to heal without scarring. Histopathological findings include granulomatous perifolliculitis and involvement of sweat glands by granulomatous inflammation.59 Lichen scrofulosorum has been documented following the administration of BCG and in patients with AIDS.60,61 Nodular tuberculid shows clinicopathological features of EIB and PNT.12 The skin lesions comprise a few to many dull red or bluish-red, and non-tender nodules of approximately 1cm in diameter that show a preference for the legs in children (Fig. 47.7).12 Ulceration is absent. Histopathological features include necrosis, granulomatous inflammation, and occasionally vasculitis, usually in the superficial dermis. Nodular tuberculid has been documented in HIV-infected patients.62
OTHER Phlebitic tuberculid or nodular granulomatous phlebitis is characterized by subcutaneous nodules along the course of leg veins.63 Histopathological examination of skin biopsies shows granulomatous inflammation within the walls of cutaneous veins. More advanced lesions show associated granulomatous panniculitis. Erythema nodosum is not a form of cutaneous TB, but represents a hypersensitivity reaction of unknown pathogenesis. Erythema nodosum can be associated with a wide spectrum of bacterial infections including mycobacteria; fungal infections; viral infections; and chlamydial infections.64 Non-infectious associations include drugs; sarcoidosis; inflammatory bowel disease; Behc¸et’s disease; and underlying neoplastic diseases such as lymphoma, leukaemia, and carcinoma. In more than 30% of cases of erythema nodosum the association remains unknown. Typical skin lesions present as a panniculitis, which manifests as tender, non-ulcerating erythematous nodules and which has a preference for the shins and less commonly the upper limbs, plantar regions, or the trunk. It must be distinguished from erythema induratum. The typical histopathological features include septal panniculitis with limited inflammation of the lobular fat. Necrosis, well-developed granulomatous inflammation, or vasculitis is absent or mild. Patients who present with erythema nodosum should be investigated for known associated diseases including TB, but a diagnosis of TB should not be based solely on the presence of erythema nodosum.
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Dermatological manifestations of tuberculosis in adults and children
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D
E Fig. 47.4 Cutaneous TB, papulonecrotic tuberculid type. Note the characteristic papular lesions with an umbilicated appearance due to central necrosis and ulceration (A, B). Note typical involvement of the ears (C) as well as associated scrofuloderma (D; arrow). A Koebner phenomenon (arrow) may infrequently be present (E). (F) Cutaneous TB, papulonecrotic tuberculid type, in a patient with HIV/AIDS. Note the confluence of papulonecrotic lesions to form larger plaques and erosions. The histopathological features are very characteristic of PNT, but are not diagnostic per se.
DIAGNOSIS A clinical diagnosis of cutaneous TB can be made with reasonable confidence in most instances. The diagnosis should be confirmed by a skin biopsy, microbiological culture in broth-based culture medium, or molecular techniques such as PCR.65 Suitable material for identification of the organism can be obtained by skin biopsy or
fine needle aspiration (FNA) of associated enlarged lymph nodes.66,67 Tuberculin skin testing in suspected cutaneous TB should not be performed in children under the age of 5 years if phlyctenular conjunctivitis is present (Fig. 47.8). The latter is associated with extreme hypersensitivity to tuberculin and a subsequent risk for ulceration and scarring following a tuberculin skin test. A strongly positive tuberculin test is highly suggestive of TB in young children. Ulceration can be prevented in these patients by
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► ►
*
*
* C
*
D
Fig. 47.5 Cutaneous TB, erythema induratum of Bazin/nodular vasculitis type is characterized by indurated and violaceous nodules that occur preferentially on the legs, especially the calves (A, B). The lesions may ulcerate and heal with scarring. Histopathology of erythema induratum of Bazin/ nodular vasculitis-type TB shows typical septolobular panniculitis with necrosis (*), granulomatous inflammation (arrow tip), and vasculitis (arrow) (C, D).
the application of a strong topical steroid to the cutaneous test site. Interpretation of the tuberculin skin test in adults is controversial and fraught with difficulties ascribed to previous BCG and the high prevalence of TB. A tuberculin skin test could, however, be performed in adults in low-TB-incidence settings where BCG is often not administered and TB is clinically suspected. Cutaneous TB is often the first clinical manifestation of underlying systemic and organ TB of, for example, the lung, bones, and urogenital tract.6 Thorough clinical examination and appropriate special investigations to search for systemic or organ TB are therefore mandatory in all patients with cutaneous TB. In patients with possible cutaneous TB based on clinicopathological findings but without demonstrable systemic or organ TB, a therapeutic test
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with the administration of full anti-TB treatment for at least 6 weeks is indicated (see Table 47.2). In the event of a clinical response to anti-TB treatment, a diagnosis of cutaneous TB is confirmed and a full course of treatment is justified. Lack of a clinical response requires clinical reassessment of the patient. In the authors’ experience this scenario is fortunately unusual. The clinical work-up of a patient with suspected cutaneous TB should include at least a thorough clinical examination of the patient and a chest radiograph. Further investigations such as FNA of enlarged lymph nodes, microscopy and culture of different specimens such as sputum, gastric aspirates, urine, endometrial fluid, bone scans, and other appropriate investigations should be directed by the clinical suspicion of underlying organ TB.
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Dermatological manifestations of tuberculosis in adults and children
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Based on the results of clinical examination and additional investigations and tests, it is possible in most cases to classify the patients according to the criteria in Table 47.2, which can be used to determine further management and treatment of the patients.
DIFFERENTIAL DIAGNOSIS
Fig. 47.6 Cutaneous TB, lichen scrofulosorum type shows characteristic small flat-topped and folliculocentric papules. The small black dots (arrows) represent hair follicle infundibulae.
The differential diagnosis for cutaneous TB will vary according to the respective clinical variants and their clinical manifestations. A comprehensive discussion of the differential diagnoses could therefore include a very extensive range of dermatological disorders, which is beyond the scope of this chapter. Box 47.1 presents a short list of relevant and common conditions to consider in the differential diagnosis of the respective variants of cutaneous TB.
TREATMENT
Fig. 47.7 Nodular tuberculid type TB is characterized by dull red or bluish-red, and non-tender nodules of approximately 1 cm in diameter that show a preference for the legs in children.
Fig. 47.8 Phlyctenular conjunctivitis is associated with extreme hypersensitivity to tuberculin and a potential severe skin reaction and ulceration to a tuberculin test.
Cutaneous TB includes all forms of TB affecting the skin – those in which organisms can be identified (tuberculous ulcer, scrofuloderma, orificial TB, TB verrucosa cutis, and lupus vulgaris) as well as those conditions formerly called ‘tuberculids’ (erythema induratum, papulonecrotic tuberculid, and lichen scrofulosorum). In all cases, tissue biopsies for culture should be performed. Often in the later conditions, cultures and PCR studies fail to detect mycobacteria, but anti-TB treatment is still indicated. Despite Finsen being awarded the Nobel Prize for his invention of light therapy for cutaneous TB, there is currently no role for light therapy in the management of cutaneous TB and the cornerstone for therapy remains modern anti-TB drugs. All patients with cutaneous TB should receive multidrug therapy as recommended in their community for active TB. Duration of therapy should be at least 6 months. Single-drug treatments and shorter courses are not recommended. There is no special protocol for the treatment of cutaneous TB. Treatment of patients should be according to standard protocols as defined by the WHO or relevant national TB control programmes. The cost of treatment for TB may be paid for by local health departments, and protocols may vary from community to community, depending on the status of drug resistance in that community at that time. The most appropriate treatment protocol for a particular patient should therefore be determined by the clinician in accordance with official guidelines at that particular time and in that particular region. If cultures grow M. tuberculosis, susceptibility studies should guide anti-TB treatment. Most cases of TB are a manifestation of systemic involvement. The bacillary load in cutaneous TB is less than that in pulmonary TB. Treatment regimens are similar to that of TB in general.68 Fixed dose combination treatment with four drugs for 2 months in the intensive phase and two drugs for 4 months in the continuation phase is the treatment of choice for adults and children over the age of 8 years. A response of skin lesions is usually witnessed within 6 weeks. If there is no visible response after 6 weeks, the patient should be re-evaluated. Careful inquiry about compliance is essential. Children with cutaneous TB are treated with isoniazid, rifampicin, and pyrazinamide for 2 months followed by isoniazid and rifampicin for 4 months (WHO Regimen III – see Chapter 61).69
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Box 47.1 Differential diagnoses of various types of cutaneous tuberculosis
Tuberculous chancre ○ Tularaemia ○ Sporotrichosis ○ Cat scratch fever ○ Mycobacterium marinum infection ○ Syphilis. Tuberculosis verrucosa cutis ○ Blastomycosis ○ Chromoblastomycosis ○ Actinomycosis ○ Leishmaniasis ○ Tertiary syphilis ○ Hypertrophic lichen planus ○ Lichen simplex chronicus ○ Lesions caused by environmental (non-tuberculous) mycobacteria ○ Bromoderma ○ Hyperkeratotic lesions due to other mycobacteria. Lupus vulgaris ○ Lymphocytoma cutis ○ Spitz naevus ○ Lupus erythematosus ○ Leishmaniasis ○ Rosacea ○ Port-wine stain ○ Lesions caused by environmental (non-tuberculous) mycobacteria ○ Leprosy ○ Sarcoidosis ○ Psoriasis ○ Bowen’s disease ○ Lichen simplex chronicus ○ Wegener’s granulomatosis ○ Blastomycosis. Tuberculosis cutis orificialis ○ Secondary syphilis ○ Aphthous ulcers ○ Carcinoma ○ Herpes virus infection.
Miliary TB with skin involvement is treated with four drugs in the intensive phase and it is of utmost importance to ensure that the appropriate treatment protocol is initiated immediately (Chapter 61). A diagnosis of multidrug-resistant (MDR) TB should never be made clinically and laboratory confirmation of drug resistance is mandatory. It is difficult to demonstrate acid-fast bacilli in smears or biopsies, or to culture M. tuberculosis from cutaneous TB because most lesions are paucibacillary. A therapeutic trial of anti-TB treatment is frequently used to confirm the diagnosis in difficult cases. Previously there were no clear guidelines on when to expect a response or when to abandon a therapeutic trial. Ramam and co-workers70 showed that, when a therapeutic trial is undertaken in cutaneous TB, 6 weeks of therapy with four drugs appear adequate to prove or disprove the diagnosis. Therapeutic trials of antituberculosis treatment is not recommended in other types of tuberculosis and
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Scrofuloderma ○ Lesions caused by environmental (non-tuberculous) mycobacteria ○ Tertiary syphilis ○ Sporotrichosis ○ Actinomycosis ○ Acne conglobata ○ Hidradenitis suppurativa. Miliary cutaneous tuberculosis ○ Disseminated BCG infection ○ Bacterial folliculitis ○ Fungal folliculitis ○ Disseminated histoplasmosis ○ Papular and papulopustular syphilides. Tuberculous gumma (metastatic tuberculous abscess) ○ Panniculitis ○ Deep fungal infections ○ Tertiary syphilis ○ Hidradenitis suppurativa. Papulonecrotic tuberculid ○ Pityriasis lichenoides ○ Leucocytoclastic vasculitis ○ Papular urticaria ○ Secondary syphilis ○ Folliculitis ○ Perforating granuloma annulare. Erythema induratum of Bazin/nodular vasculitis ○ Other forms of panniculitis. Lichen scrofulosorum ○ Lichen nitidus ○ Keratosis pilaris ○ Papular or lichenoid sarcoidosis ○ Lichenoid secondary syphilis ○ Drug eruptions ○ Lichen planus. Nodular tuberculid ○ Insect bites ○ Evolving folliculitis ○ Evolving vasculitis ○ Dermal erythema multiforme.
should therefore not be done if any other systemic form of tuberculosis co-exists.
CONCLUSION Cutaneous manifestations of TB are relatively common in countries with a high prevalence of TB and may be the presenting clinical manifestation of the disease. Underlying systemic TB is often subtle and may be difficult to demonstrate. It is therefore of great importance that clinicians are familiar with the clinicopathological spectrum of cutaneous TB and that they maintain a high index of suspicion for underlying TB in patients with skin lesions as described in this chapter. A pragmatic approach to the diagnosis and management of cutaneous TB as outlined in the relevant table should facilitate and simplify optimal clinical care of patients.
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Dermatological manifestations of tuberculosis in adults and children
REFERENCES 25. 1. Beutner EH. Tuberculosis of the skin: historical perspectives on tuberculin and Bacillus Calmette Guerin. Int J Dermatol 1997;36:73–77. 2. Moller KI, Kongshoj B, Philipsen PA, et al. How Finsen’s light cured lupus vulgaris. Photodermatol Photoimmunol Photomed 2005; 21:118–124. 3. Beyt BE Jr, Ortbals DW, Santa Cruz DJ, et al. Cutaneous mycobacteriosis: analysis of 34 cases with a new classification of the disease. Medicine (Baltimore) 1981;60:95–109. 4. Zumla A, Malon P, Henderson J, et al. Impact of HIV infection on tuberculosis. Postgrad Med J 2000;76:259–268. 5. Inwald D, Nelson M, Cramp M, et al. Cutaneous manifestations of mycobacterial infection in patients with AIDS. Br J Dermatol 1994;130:111–114. 6. Kivanc-Altunay I, Baysal Z, Ekmekci TR, et al. Incidence of cutaneous tuberculosis in patients with organ tuberculosis. Int J Dermatol 2003; 42:197–200. 7. Hay RJ. Cutaneous infection with Mycobacterium tuberculosis: how has this altered with the changing epidemiology of tuberculosis? Curr Opin Infect Dis 2005;18:93–95. 8. Foo CC, Tan HH. A case of tuberculosis verrucosa cutis–undiagnosed for 44 years and resulting in fixedflexion deformity of the arm. Clin Exp Dermatol 2005;30:149–151. 9. Sharma S, Choudhary R, Juneja M, et al. Cutaneous tuberculosis mimicking sporotrichosis. Indian J Pediatr 2005;72:86. 10. Ho CK, Ho MH, Chong LY. Cutaneous tuberculosis in Hong Kong: an update. Hong Kong Med J 2006;12:272–277. 11. Kakakhel KU, Fritsch P. Cutaneous tuberculosis. Int J Dermatol 1989;28:355–362. 12. Yates VM, Rook GAW. In: Burns T (ed.). Rook’s Textbook of Dermatology. London: Blackwell, 2004: 1–38. 13. Jordaan HF, Schneider JW, Abdulla EA. Nodular tuberculid: a report of four patients. Pediatr Dermatol 2000;17:183–188. 14. Peart LK, Schneider JW, Jordaan HF, et al. Fine needle aspiration biopsy of postvaccination disseminated Mycobacterium bovis infection presenting as a solitary cutaneous papule. Acta Cytol 2005;49:230–231. 15. Antaya RJ, Gardner ES, Bettencourt MS, et al. Cutaneous complications of BCG vaccination in infants with immune disorders: two cases and a review of the literature. Pediatr Dermatol 2001;18:205–209. 16. Atasoy M, Aliagaoglu C, Erdem T, et al. Scrofuloderma following BCG vaccination. Pediatr Dermatol 2005;22:179–180. 17. Figueiredo A, Poiares-Baptista A, Branco M, et al. Papular tuberculids post-BCG vaccination. Int J Dermatol 1987;26:291–294. 18. Inoue T, Fukumoto T, Ansai S, et al. Erythema induratum of Bazin in an infant after Bacillus Calmette-Guerin vaccination. J Dermatol 2006;33:268–272. 19. Handjani F, Delir S, Sodaifi M, et al. Lupus vulgaris following bacille Calmette-Guerin vaccination. Br J Dermatol 2001;144:444–445. 20. Park YM, Kang H, Cho SH, Cho BK. Lichen scrofulosorum-like eruption localized to multipuncture BCG vaccination site. J Am Acad Dermatol 1999;41:262–264. 21. Saxe N. Mycobacterial skin infections. J Cutan Pathol 1985;12:300–312. 22. Pereira J. [Tuberculids]. Rev Port Pneumol 2004;10:97–105. 23. Jepson A, Fowler A, Banya W, et al. Genetic regulation of acquired immune responses to antigens of Mycobacterium tuberculosis: a study of twins in West Africa. Infect Immun 2001;69:3989–3994. 24. Ramdial PK, Mosam A, Mallett R, et al. Papulonecrotic tuberculid in a 2-year-old girl: with
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emphasis on extent of disease and presence of leucocytoclastic vasculitis. Pediatr Dermatol 1998;15:450–455. Schneider JW, Jordaan HF. The histopathologic spectrum of erythema induratum of Bazin. Am J Dermatopathol 1997;19:323–333. Daikos GL, Uttamchandani RB, Tuda C, et al. Disseminated miliary tuberculosis of the skin in patients with AIDS: report of four cases. Clin Infect Dis 1998;27:205–208. Jordaan HF, Schneider JW, Schaaf HS, et al. Papulonecrotic tuberculid in children. A report of eight patients. Am J Dermatopathol 1996; 18: 172–185. Schneider JW, Geiger DH, Rossouw DJ, et al. Mycobacterium tuberculosis DNA in erythema induratum of Bazin. Lancet 1993;342:747–748. Schneider JW, Jordaan HF, Geiger DH, et al. Erythema induratum of Bazin. A clinicopathological study of 20 cases and detection of Mycobacterium tuberculosis DNA in skin lesions by polymerase chain reaction. Am J Dermatopathol 1995;17: 350–356. Pino GM, Velasco M, Vilata JJ, et al. Primary tuberculous chancre: an unusual kind of skin tuberculosis. J Am Acad Dermatol 1994; 31:108–109. Goette DK, Jacobson KW, Doty RD. Primary inoculation tuberculosis of the skin. Prosector’s paronychia. Arch Dermatol 1978;114:567–569. Pereira MB, Gomes MK, Pereira F. Tuberculosis verrucosa cutis associated with tuberculous lymphadenitis. Int J Dermatol 2000;39:856–858. Wozniacka A, Schwartz RA, Sysa-Jedrzejowska A, et al. Lupus vulgaris: report of two cases. Int J Dermatol 2005;44:299–301. Miteva L. Alopecia: a rare manifestation of lupus vulgaris. Int J Dermatol 2001;40:659–661. Aliagaoglu C, Atasoy M, Karakuzu A, et al. Rapidly developing giant sized lupus vulgaris on the chest associated with bilateral scrofuloderma on the neck. J Dermatol 2006;33:481–485. Jaisankar TJ, Garg BR, Reddy BS, et al. Penile lupus vulgaris. Int J Dermatol 1994;33:272–274. Sammain A, Jocher A, Bruckner-Tuderman L, et al. Lupus vulgaris—a case diagnosed more than 20 years after onset. J Dtsch Dermatol Ges 2006; 4:958–960. Kanitakis J, Audeffray D, Claudy A. Squamous cell carcinoma of the skin complicating lupus vulgaris. J Eur Acad Dermatol Venereol 2006;20:114–116. Sowden J, Paramsothy Y, Smith AG. Malignant melanoma arising in the scar of lupus vulgaris and response to treatment with topical azelaic acid. Clin Exp Dermatol 1988;13:353–356. Sammain A, Jocher A, Bruckner-Tuderman L, et al. Lupus vulgaris: a case diagnosed more than 20 years after onset. J Dtsch Dermatol Ges 2006;4:958–960. Ichihashi K, Katoh N, Takenaka H, et al. Orificial tuberculosis: presenting as a refractory perianal ulcer. Acta Derm Venereol 2004;84:331–332. Ejaz A, Aurangzeb, Awan Z. Scrofuloderma neck with chest wall abscess. J Coll Physicians Surg Pak 2006;16:420–421. Zouhair K, Akhdari N, Nejjam F, et al. Cutaneous tuberculosis in Morocco. Int J Infect Dis 2007; 11:209–212. Mert A, Bilir M, Ozturk R, et al. Tuberculous subcutaneous abscesses developing during miliary tuberculosis therapy. Scand J Infect Dis 2000; 32:37–40. High WA, Evans CC, Hoang MP. Cutaneous miliary tuberculosis in two patients with HIV infection. J Am Acad Dermatol 2004;50:S110–S113. Antinori S, Galimberti L, Tadini GL, et al. Tuberculosis cutis miliaris disseminata due to multidrug-resistant Mycobacterium tuberculosis in AIDS patients. Eur J Clin Microbiol Infect Dis 1995; 14:911–914. Kalaria VG, Kapila R, Schwartz RA. Tuberculous gumma (cutaneous metastatic tuberculous abscess) with underlying lymphoma.Cutis 2000;66:277–279.
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48. Barbagallo J, Tager P, Ingleton R, et al. Cutaneous tuberculosis: diagnosis and treatment. Am J Clin Dermatol 2002;3:319–328. 49. Victor T, Jordaan HF, Van Niekerk DJ, et al. Papulonecrotic tuberculid. Identification of Mycobacterium tuberculosis DNA by polymerase chain reaction. Am J Dermatopathol 1992;14:491–495. 50. Degitz K. Detection of mycobacterial DNA in the skin. Etiologic insights and diagnostic perspectives. Arch Dermatol 1996;132:71–75. 51. Ramdial PK, Mosam A, Pillay T, et al. Childhood Lichen scrofulosorum revisited. Pediatr Dev Pathol 2000;3:211–215. 52. Park YM, Hong JK, Cho SH, et al. Concomitant lichen scrofulosorum and erythema induratum. J Am Acad Dermatol 1998;38:841–843. 53. Israelewicz S, Dharan M, Rosenman D, et al. Papulonecrotic tuberculid of the glans penis. J Am Acad Dermatol 1985;12:1104–1106. 54. Iden DL, Rogers RS III, Schroeter AL. Papulonecrotic tuberculid secondary to Mycobacterium bovis. Arch Dermatol 1978;114:564–566. 55. Jordaan HF, Van Niekerk DJ, Louw M. Papulonecrotic tuberculid. A clinical, histopathological, and immunohistochemical study of 15 patients. Am J Dermatopathol 1994;16:474–485. 56. Wilson-Jones E, Winkelmann RK. Papulonecrotic tuberculid: a neglected disease in Western countries. J Am Acad Dermatol 1986;14:815–826. 57. Rademaker M, Lowe DG, Munro DD. Erythema induratum (Bazin’s disease). J Am Acad Dermatol 1989;21:740–745. 58. Singal A, Bhattacharya SN. Lichen scrofulosorum: a prospective study of 39 patients. Int J Dermatol 2005;44:489–493. 59. Beena KR, Ramesh V, Mukherjee A. Lichen scrofulosorum—a series of eight cases. Dermatology 2000;201:272–274. 60. Kumaran MS, Dogra S, Kaur I, et al. Lichen scrofulosorum in a patient with lepromatous leprosy after BCG immunotherapy. Lepr Rev 2005; 76:170–174. 61. Arianayagam AV, Ash S, Jones RR. Lichen scrofulosorum in a patient with AIDS. Clin Exp Dermatol 1994;19:74–76. 62. Friedman PC, Husain S, Grossman ME. Nodular tuberculid in a patient with HIV. J Am Acad Dermatol 2005;53:S154–S156. 63. Hara K, Tsuzuki T, Takagi N, et al. Nodular granulomatous phlebitis of the skin: a fourth type of tuberculid. Histopathology 1997;30:129–134. 64. Schwartz RA, Nervi SJ. Erythema nodosum: a sign of systemic disease. Am Fam Physician 2007; 5:695–700. 65. Negi SS, Basir SF, Gupta S, et al. Comparative study of PCR, smear examination and culture for diagnosis of cutaneous tuberculosis. J Commun Dis 2005; 37:83–92. 66. Kathuria P, Agarwal K, Koranne RV. The role of fine-needle aspiration cytology and Ziehl Neelsen staining in the diagnosis of cutaneous tuberculosis. Diagn Cytopathol 2006;34:826–829. 67. Marais BJ, Wright CA, Schaaf HS, et al. Tuberculous lymphadenitis as a cause of persistent cervical lymphadenopathy in children from a tuberculosis-endemic area. Pediatr Infect Dis J 2006;25:142–146. 68. Barbagallo J, Tager P, Ingleton R, et al. Cutaneous tuberculosis: diagnosis and treatment. Am J Clin Dermatol 2002;3:319–328. 69. Sehgal VN, Sardana K, Sehgal R, et al. The use of anti-tubercular therapy (ATT) as a diagnostic tool in pediatric cutaneous tuberculosis. Int J Dermatol 2005;44:961–963. 70. Ramam M, Mittal R, Ramesh V. How soon does cutaneous tuberculosis respond to treatment? Implications for a therapeutic test of diagnosis. Int J Dermatol 2005;44:121–124.
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Dermatological manifestations of tuberculosis in adults and children H Francois Jordaan and Johann W Schneider
INTRODUCTION The late eighteenth and early nineteenth centuries are known as the Age of Reason and the era of the establishment of dermatology as a specialty. At that time, Willan and Bateman set forth accurate descriptions of the basic types of skin lesions. Initially skin lesions were grouped into ‘orders’ and ‘genera’. Skin lesions of TB appeared in the order of ‘tubercles’ and in the genus of ‘lupus’. With the Age of Reason came the Industrial Revolution and the three key factors that lead to a rapid increase in the incidence of TB, namely urban congestion, poverty, and a susceptible population. By the midnineteenth century, TB killed about one-quarter of young adults in industrialized countries. The high death rate from birth to the age of 6 or 7 years was due to bovine TB transmitted by raw milk. The second peak in the death rate was between the ages of 25 and 50 years. This was due to human tubercle bacilli transmitted largely by droplet infection. Also by this time, dermatologists had begun to differentiate between localized cutaneous TB and skin manifestations of systemic TB, and to classify skin lesions of TB based on their morphology. Worcester classified TB lesions involving both the skin and deeper tissues as ‘lupus exedens’ and TB confined to the skin as ‘lupus non-exedens’. In 1876 Neligan described cases with localized skin lesions as ‘lupus superficialis’ and ‘lupus serpiginosus’ and cases with skin lesions and ‘scrofula’ (TB of lymph nodes) associated with TB of deeper tissues as ‘lupus devorans’. Fox and Duhring referred to TB of the skin simply as ‘lupus vulgaris’. Robert Koch reported on his bacteriological findings of TB in 1882. He stained and cultured tubercle bacilli and reported the transfer of TB to animals with these cultures. Koch’s postulates provide the key method for identifying the causative agent of all forms of TB of the skin.1 In 1903, Niels Ryberg Finsen was awarded the Nobel Prize for his invention of light therapy for cutaneous TB (lupus vulgaris). It was recently demonstrated that Mycobacterium tuberculosis produces coproporphyrin III. Radiation with light of 400 nm led to the production of singlet oxygen.2 Since these early days, various classifications have been proposed for cutaneous TB. However, it was the classification of Beyt et al.3 and minor modifications of this classification that gained general approval. The global expansion of TB during the past decade confirms that TB is a growing health problem, especially in populations with a high prevalence of human immunodeficiency virus (HIV) infection.4 The acquired immunodeficiency syndrome (AIDS) pandemic and increased number of immunocompromised patients
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contribute significantly to the increased incidence of TB and its cutaneous manifestations.5,6 Many recent publications emphasize this phenomenon and highlight the importance of cutaneous manifestations of TB as an important clinical and diagnostic challenge.6,7 Cutaneous TB can mimic the clinicopathological features of many other skin diseases, and underlying systemic or organ TB can be notoriously difficult to detect, resulting in considerable diagnostic challenges and pitfalls and potential delays in diagnosis and institution of treatment.8,9 Patient immunity to M. tuberculosis, previous infection, and the route of infection determine the clinicopathological features of cutaneous TB in a particular patient. Systemic TB is present in the overwhelming majority of patients, and direct cutaneous or mucosal inoculation with M. tuberculosis is rare.6,10 Cutaneous manifestations of TB include a wide and often overlapping spectrum of papules, pustules, papulonecrotic and papulopustular lesions, nodules, panniculitis, plaques, verrucous lesions, ulcers, chronic sinuses, and scars.11
CLASSIFICATION OF CUTANEOUS TUBERCULOSIS Over the years, a number of classifications of cutaneous TB have been proposed. Accurate classification of the varied expressions of cutaneous TB is relevant in order to improve diagnostic accuracy and appropriate prognostication and treatment of patients.11 The classification of Beyt et al.3 gained general acceptance, and a modification of this classification has been utilized in the latest edition of Rook’s Textbook of Dermatology.12 More recent modifications of the classification adhere to the route of infection, but acknowledge the expanding spectrum of cutaneous TB and include tuberculids as a variant of cutaneous TB rather than a cutaneous hypersensitivity reaction to underlying systemic or organ TB (Table 47.1).13 Complications of Bacillus Calmette–Gue´rin (BCG) vaccination include disseminated infection with spread to the skin,14,15 scrofuloderma,16 papular tuberculids,17 erythema induratum,18 lupus vulgaris,19 lichen scrofulosorum,20 and keloids,11 and should therefore be included in a classification of cutaneous TB (Table 47.1). Considerable clinicopathological overlap and non-specific clinical features complicate the traditional classification of cutaneous TB.3 Overlapping clinicopathological features emphasize that the traditional subtypes of cutaneous TB represent a spectrum with variable and overlapping combinations of clinical and histopathological features, variable success for detecting tuberculous bacilli in skin lesions, and variable demonstration of underlying
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Dermatological manifestations of tuberculosis in adults and children
Table 47.1 Classification of cutaneous tuberculosis Inoculation tuberculosis from exogenous source (primary cutaneous tuberculosis)
Primary tuberculous chancre Verrucosa cutis (warty TB) Some cases of lupus vulgaris-type TB
Table 47.2 A practical guide to the diagnosis and management of cutaneous tuberculosis Definite cutaneous TB Clinical morphology
Secondary tuberculosis from endogenous source
Direct spread to the skin (scrofuloderma-type TB) Autoinoculation (orificial TB)
Histopathology
Haematogenous tuberculosis
Miliary TB Some cases of lupus vulgaris-type TB Tuberculous gumma
Tuberculid-type tuberculosis (tuberculids or eruptive tuberculosis)
Papulonecrotic-type TB Erythema induratum of Bazin/nodular vasculitis-type TB Lichen scrofulosorum-type TB Nodular tuberculid
ZN and/or culture and/or PCR on skin lesion biopsy ZN and/or culture and/or PCR on specimen from origin other than skin Mantoux test result
Phlebitic tuberculid-type TB BCG-related TB
non-cutaneous TB. The clinical management of patients will depend on the level of certainty of the diagnosis of TB rather than the subtype of cutaneous TB. A more useful approach to cutaneous TB from a clinical perspective should combine clinicopathological findings and the results of special investigations to offer practical guidelines and stratification of patients as definitive, probable, and possible cutaneous TB, respectively (Table 47.2).
PATHOGENESIS AND MORPHOLOGY The genus Mycobacterium contains more than 80 species, most of which are harmless environmental saprophytes. The most important obligate human pathogens are M. tuberculosis and Mycobacterium leprae, but others such as Mycobacterium avium and Mycobacterium ulcerans are also significant. These are now best referred to as environmental mycobacteria, also referred to as non-tuberculous mycobacteria (NTM). Cutaneous involvement by M. tuberculosis can follow direct inoculation of organisms from an exogenous source; direct spread of organisms from an endogenous source such as tuberculous lymphadenitis extending to the skin (scrofuloderma) or autoinoculation, e.g. mucocutaneous involvement from pulmonary TB (orificial TB); haematogenous dissemination of organisms from a distant site; or haematogenous spread of mycobacterial components including DNA as seen in the so-called tuberculids.21,22 These various pathogenic mechanisms are further modulated by the number and the virulence of the organisms and the concerned host’s level of immune competence and genetic predisposition to infection. These complex interactions between host
Radiograph findings compatible with TB, e.g. lung, bone Response to anti-TB treatment
Probable cutaneous TB
Possible cutaneous TB
Variable combinations and transitions of papular, nodular, pustular, papulonecrotic, pustulonecrotic, ulcerative, vegetating skin lesions Variable combinations and transitions of granulomatous inflammation, mixed acute and chronic inflammatory cells, necrosis, vasculitis, organization and fibrosis, other non-specific changes – – +a
NEFD
+b
–
NEFD
–
NEFD
+b (only in children <5 years old) +b
NEFD
NEFD
EFD
Other
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–
ZN, Ziehl–Neelsen stain; PCR, polymerase chain reaction; NEFD, not essential for diagnosis; EFD, essential for diagnosis (but not necessarily proof of TB). a When only ZN positive, distinction from environmental (nontuberculous) mycobacteria is necessary by culture and/or PCR. b Any positive establishes the diagnosis of probable TB.
factors on the one hand and the organism and other environmental factors on the other hand result in the wide spectrum of clinicopathological manifestations of cutaneous TB.23 The microscopic hallmark of cutaneous TB is granulomatous inflammation, which may vary from sarcoidal or tuberculoid granulomas to necrotizing, suppurative, or palisading granulomas. Combinations of various patterns of granulomatous inflammation are common. In some cases of erythema induratum of Bazin and papulonecrotic tuberculid, necrotizing vasculitis is present.24,25 The epidermis may be atrophic, hyperplastic, or ulcerated. Lymphocytes, macrophages, plasma cells, and sometimes neutrophils and eosinophils constitute the inflammatory cell population involved. Scarring may be mild, moderate, or marked. Although the histopathological findings are often quite characteristic, they are not diagnostic per se and a specific diagnosis depends on clinicopathological correlation and the demonstration of M. tuberculosis organisms in skin lesions or other organs. The detection of M. tuberculosis organisms in skin lesions depends largely on the type of cutaneous involvement and the adequacy of the diagnostic sample tissue. Organisms are usually easy to detect in skin lesions associated with miliary TB or scrofuloderma, difficult to find in specimens obtained from lupus vulgaris lesions, and absent in tuberculids where demonstration of M. tuberculosis DNA by polymerase chain reaction (PCR) is required.26–29
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The variable and overlapping clinical and pathological features of cutaneous TB often defy the various types of clinical lesions depicted in traditional classification, leading to diagnostic challenges. Despite these limitations, an understanding of the pathogenesis and various morphological patterns of cutaneous TB facilitates the recognition of the various clinical manifestations of the disease (Table 47.1).
PRIMARY CUTANEOUS TUBERCULOSIS Primary cutaneous TB follows the direct inoculation of M. tuberculosis organisms into the skin due to penetrating trauma such as ear piercing, circumcision, tattooing, or injury to laboratory staff.30 The subsequent indurated papulonodular lesion appears within 1–3 weeks and tends to ulcerate, resulting in a primary chancre and regional lymphadenopathy, similar to the pulmonary Ghon complex. A similar picture can follow BCG vaccination.21 Biopsies from a primary chancre reveal mixed acute and chronic inflammation that leads to necrosis, ulceration, and granulomatous inflammation after a
few weeks.31 Organisms are easily demonstrated in tissue sections by Ziehl–Neelsen stain. Underlying systemic TB is absent. Inoculation of M. tuberculosis bacteria into the skin of patients with strong immunity may lead to TB verrucosa cutis.32 This unusual expression of cutaneous TB is characterized initially by a warty indurated nodule that expands in time to form a verrucous plaque. The skin lesions typically involve the dorsum of the hand or fingers following exposure to infected tissues or sputum. Pathological findings include epidermal hyperplasia, hyperkeratosis, papillomatosis, and mixed acute and chronic inflammation with caseating granulomas in the dermis. Ziehl–Neelsen stain of tissue sections will usually show sparse bacilli. Lupus vulgaris can follow inoculation of organisms into the skin of patients with previous or current TB, but, more often, it follows haematogenous or lymphatic dissemination to the skin from underlying and often subclinical TB. Less commonly it may develop at the site of BCG inoculation.33 The skin lesions are characterized by coalescing papules that form a plaque that has traditionally been described as resembling apple jelly nodules on diascopy (Fig. 47.1).
Fig. 47.1 Cutaneous TB, lupus vulgaris variant involving the tip of the nose (A) and the nose and upper lip (B). The nose is a characteristic site of involvement. The differential diagnosis in (B) should include discoid lupus erythematosus. Plaques are often a typical clinical manifestation of lupus vulgaris as demonstrated in this lesion involving the arm and showing an expanding nodular border with central atrophic scarring (C). Note the central atrophy and scarring in this example of lupus vulgaris involving the lateral neck (D).
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Dermatological manifestations of tuberculosis in adults and children
Other clinical manifestations include warty plaques, ulceration, cellulitis, and rarely alopecia.34 Although the head and neck and especially the nose are typically involved, lupus vulgaris may less commonly involve the limbs and feet, gluteal area, trunk,35 and penis.36 Disseminated lesions may also occur. Lupus vulgaris is a chronic condition, and it is often characterized by considerable delay in arriving at the correct diagnosis.37 Subsequent scar formation is therefore not uncommon. Squamous cell carcinoma and less commonly basal cell carcinoma, melanoma, and lymphoma may complicate long-standing lupus vulgaris.38,39 Histopathological features include intradermal tuberculoid granulomas with little or no necrosis, mimicking sarcoidosis.40 Pseudoepitheliomatous hyperplasia of the epidermis may simulate squamous cell carcinoma, especially in superficial biopsies. Less frequently, epidermal atrophy and ulceration may be present. Organisms are usually rare and difficult to find in Ziehl–Neelsen-stained sections.
SECONDARY TUBERCULOSIS FROM ENDOGENOUS SOURCE Orificial tuberculosis is characterized by ulceration at mucocutaneous orifices including the mouth, nose, perianal region, and genitalia (Fig. 47.2).41 The clinical lesions follow autoinoculation of the mucocutaneous surface from underlying active TB with abundant organisms. Patients present with persistent and undermined painful ulcers. Biopsies of the ulcers typically show prominent necrosis with
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Fig. 47.2 Orificial TB with involvement of the tongue.
mixed acute and chronic inflammation and inconspicuous granulomas. Ziehl–Neelsen-stained sections reveal abundant organisms. Scrofuloderma represents direct spread to the skin from underlying tuberculous infection such as tuberculous lymphadenitis, arthritis, or osteomyelitis.42,43 Typical lesions include ulcerating nodules, ulcers, draining sinuses, and scarring (Fig. 47.3). Frequently involved sites include the neck and submandibular regions, but many sites could be involved, depending on the location of the focus of TB. Active TB is present and histological findings typically
Fig. 47.3 Cutaneous TB, scrofuloderma variant. Note the extensive ulceration and draining sinuses in the inguinal region (A) and the underlying lymphadenopathy and linear arrangement ulceration on the lateral side of the neck (B) and the superficial scarring (C). The linear arrangement corresponds to the lymphatic drainage in this area.
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CLINICAL PRESENTATIONS OF TUBERCULOSIS
demonstrate ulceration, caseating granulomas, abscess formation, and variable number of acid-fast bacilli.
HAEMATOGENOUS TUBERCULOSIS Miliary TB has a poor prognosis if not diagnosed and treated timeously and usually occurs in infants and children and follows haematogenous dissemination of numerous M. tuberculosis organisms from underlying active TB usually in the lung. Typical skin lesions include papules, pustules, vesiculopustular lesions, small ulcers, haemorrhagic lesions, and subcutaneous abcesses.44 Miliary TB may occur in immunocompromised patients, including patients with AIDS.45 Lesions that simulate folliculitis may cause diagnostic problems.46 A high index of suspicion is important to establish a diagnosis. Histopathological features include necrosis, small dermal abscesses, and leucocytoclastic vasculitis, often without granulomatous inflammation.45 Since underlying TB is often not suspected clinically, the histopathological features could be interpreted as non-specific. However, Ziehl–Neelsen stain of tissue sections will usually show numerous acid-fast bacilli. Tuberculous gumma (metastatic tuberculous abscess) follows haematogenous dissemination of organisms from a tuberculous focus elsewhere in the body to the subcutaneous tissue with subsequent development of a subcutaneous abscess.47 Patients with malnutrition and compromised immunity are more frequently affected.48 The clinical features include one or more subcutaneous nodules that may soften because of necrosis. Subsequent chronic ulceration may simulate scrofuloderma. Biopsies from affected sites reveal granulomatous inflammation, often with extensive caseous necrosis, that involves primarily the subcutaneous tissue with extension to the dermis. Ziehl–Neelsen stain typically shows sparse bacilli.
TUBERCULIDS Tuberculids include a spectrum of related and often overlapping clinicopathological manifestations of cutaneous TB that occur in patients with tuberculin hypersensitivity and with underlying and often subclinical tuberculous infection elsewhere in the body.12,29 Mycobacterium tuberculosis organisms are absent in the skin lesions when assessed by Ziehl–Neelsen stains and culture, but M. tuberculosis DNA can be demonstrated by PCR in 25–50% of cases.28,29,49,50 A good clinical response of the skin lesions to anti-TB treatment provides further evidence that the tuberculids are best regarded as a variant of cutaneous TB rather than an immunological reaction to TB elsewhere in the body, including BCG.12,29,51 Clinicopathological variants of tuberculid-type cutaneous TB include papulonecrotic tuberculid (PNT), erythema induratum of Bazin (EIB), lichen scrofulosorum, nodular tuberculid, and nodular granulomatous phlebitis. Concurrent lesions of different expressions of tuberculid-type TB overlapping histopathological features suggest that these clinicopathological variants form part of a single spectrum of disease.12,52 PNT is characterized by recurring crops of skin-coloured or red papules that can show central necrosis, ulceration, crusts, and pustules that heal in time with small depressed scars (Fig. 47.4A–D). The skin lesions can occur in children and in adults and they typically involve the ears and extensor surfaces of the limbs around the elbows and knees.12,21,27 The lesions may be symmetrical and widespread or localized to specific areas such as the penis.53 Occasionally a Koebner phenomenon may occur (Fig. 47.4E). Confluence and
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ulceration of the lesions may occur in patients with AIDS (Fig. 47.4F). PNT may follow BCG vaccination.54 Histopathological features include wedge-shaped necrosis of the upper dermis with the base towards the epidermis which frequently shows ulceration.27,55,56 The area of necrosis is often folliculocentric and flanked by granulomatous inflammation and chronic inflammatory cells (Fig. 47.4).55 Leucocytoclastic vasculitis may be present.24 Ziehl– Neelsen stain for acid-fast bacilli is always negative. Erythema induratum of Bazin or erythema induratum/nodular vasculitis is a form of panniculitis characterized by red violaceous nodules that classically occur on the calves of women especially in winter (Fig. 47.5A and B).57 The nodules may be painful and undergo ulceration that tends to be chronic and to heal with scarring. Biopsies from EIB skin lesions reveal variable features of septolobular panniculitis, necrosis, granulomatous inflammation, and vasculitis of smaller or larger blood vessels (Fig. 47.5C and D).25,57 Acid-fast bacilli are invariably absent. Lichen scrofulosorum typically affects paediatric patients and young adults and is often associated with localized tuberculous lymphadenitis or organ TB, particularly tuberculous osteomyelitis. The condition is characterized by asymptomatic yellowish papules on the trunk (Fig. 47.6).51,58 The skin lesions tend to heal without scarring. Histopathological findings include granulomatous perifolliculitis and involvement of sweat glands by granulomatous inflammation.59 Lichen scrofulosorum has been documented following the administration of BCG and in patients with AIDS.60,61 Nodular tuberculid shows clinicopathological features of EIB and PNT.12 The skin lesions comprise a few to many dull red or bluish-red, and non-tender nodules of approximately 1cm in diameter that show a preference for the legs in children (Fig. 47.7).12 Ulceration is absent. Histopathological features include necrosis, granulomatous inflammation, and occasionally vasculitis, usually in the superficial dermis. Nodular tuberculid has been documented in HIV-infected patients.62
OTHER Phlebitic tuberculid or nodular granulomatous phlebitis is characterized by subcutaneous nodules along the course of leg veins.63 Histopathological examination of skin biopsies shows granulomatous inflammation within the walls of cutaneous veins. More advanced lesions show associated granulomatous panniculitis. Erythema nodosum is not a form of cutaneous TB, but represents a hypersensitivity reaction of unknown pathogenesis. Erythema nodosum can be associated with a wide spectrum of bacterial infections including mycobacteria; fungal infections; viral infections; and chlamydial infections.64 Non-infectious associations include drugs; sarcoidosis; inflammatory bowel disease; Behc¸et’s disease; and underlying neoplastic diseases such as lymphoma, leukaemia, and carcinoma. In more than 30% of cases of erythema nodosum the association remains unknown. Typical skin lesions present as a panniculitis, which manifests as tender, non-ulcerating erythematous nodules and which has a preference for the shins and less commonly the upper limbs, plantar regions, or the trunk. It must be distinguished from erythema induratum. The typical histopathological features include septal panniculitis with limited inflammation of the lobular fat. Necrosis, well-developed granulomatous inflammation, or vasculitis is absent or mild. Patients who present with erythema nodosum should be investigated for known associated diseases including TB, but a diagnosis of TB should not be based solely on the presence of erythema nodosum.
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Dermatological manifestations of tuberculosis in adults and children
47
D
E Fig. 47.4 Cutaneous TB, papulonecrotic tuberculid type. Note the characteristic papular lesions with an umbilicated appearance due to central necrosis and ulceration (A, B). Note typical involvement of the ears (C) as well as associated scrofuloderma (D; arrow). A Koebner phenomenon (arrow) may infrequently be present (E). (F) Cutaneous TB, papulonecrotic tuberculid type, in a patient with HIV/AIDS. Note the confluence of papulonecrotic lesions to form larger plaques and erosions. The histopathological features are very characteristic of PNT, but are not diagnostic per se.
DIAGNOSIS A clinical diagnosis of cutaneous TB can be made with reasonable confidence in most instances. The diagnosis should be confirmed by a skin biopsy, microbiological culture in broth-based culture medium, or molecular techniques such as PCR.65 Suitable material for identification of the organism can be obtained by skin biopsy or
fine needle aspiration (FNA) of associated enlarged lymph nodes.66,67 Tuberculin skin testing in suspected cutaneous TB should not be performed in children under the age of 5 years if phlyctenular conjunctivitis is present (Fig. 47.8). The latter is associated with extreme hypersensitivity to tuberculin and a subsequent risk for ulceration and scarring following a tuberculin skin test. A strongly positive tuberculin test is highly suggestive of TB in young children. Ulceration can be prevented in these patients by
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CLINICAL PRESENTATIONS OF TUBERCULOSIS
► ►
*
*
* C
*
D
Fig. 47.5 Cutaneous TB, erythema induratum of Bazin/nodular vasculitis type is characterized by indurated and violaceous nodules that occur preferentially on the legs, especially the calves (A, B). The lesions may ulcerate and heal with scarring. Histopathology of erythema induratum of Bazin/ nodular vasculitis-type TB shows typical septolobular panniculitis with necrosis (*), granulomatous inflammation (arrow tip), and vasculitis (arrow) (C, D).
the application of a strong topical steroid to the cutaneous test site. Interpretation of the tuberculin skin test in adults is controversial and fraught with difficulties ascribed to previous BCG and the high prevalence of TB. A tuberculin skin test could, however, be performed in adults in low-TB-incidence settings where BCG is often not administered and TB is clinically suspected. Cutaneous TB is often the first clinical manifestation of underlying systemic and organ TB of, for example, the lung, bones, and urogenital tract.6 Thorough clinical examination and appropriate special investigations to search for systemic or organ TB are therefore mandatory in all patients with cutaneous TB. In patients with possible cutaneous TB based on clinicopathological findings but without demonstrable systemic or organ TB, a therapeutic test
490
with the administration of full anti-TB treatment for at least 6 weeks is indicated (see Table 47.2). In the event of a clinical response to anti-TB treatment, a diagnosis of cutaneous TB is confirmed and a full course of treatment is justified. Lack of a clinical response requires clinical reassessment of the patient. In the authors’ experience this scenario is fortunately unusual. The clinical work-up of a patient with suspected cutaneous TB should include at least a thorough clinical examination of the patient and a chest radiograph. Further investigations such as FNA of enlarged lymph nodes, microscopy and culture of different specimens such as sputum, gastric aspirates, urine, endometrial fluid, bone scans, and other appropriate investigations should be directed by the clinical suspicion of underlying organ TB.
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Dermatological manifestations of tuberculosis in adults and children
47
Based on the results of clinical examination and additional investigations and tests, it is possible in most cases to classify the patients according to the criteria in Table 47.2, which can be used to determine further management and treatment of the patients.
DIFFERENTIAL DIAGNOSIS
Fig. 47.6 Cutaneous TB, lichen scrofulosorum type shows characteristic small flat-topped and folliculocentric papules. The small black dots (arrows) represent hair follicle infundibulae.
The differential diagnosis for cutaneous TB will vary according to the respective clinical variants and their clinical manifestations. A comprehensive discussion of the differential diagnoses could therefore include a very extensive range of dermatological disorders, which is beyond the scope of this chapter. Box 47.1 presents a short list of relevant and common conditions to consider in the differential diagnosis of the respective variants of cutaneous TB.
TREATMENT
Fig. 47.7 Nodular tuberculid type TB is characterized by dull red or bluish-red, and non-tender nodules of approximately 1 cm in diameter that show a preference for the legs in children.
Fig. 47.8 Phlyctenular conjunctivitis is associated with extreme hypersensitivity to tuberculin and a potential severe skin reaction and ulceration to a tuberculin test.
Cutaneous TB includes all forms of TB affecting the skin – those in which organisms can be identified (tuberculous ulcer, scrofuloderma, orificial TB, TB verrucosa cutis, and lupus vulgaris) as well as those conditions formerly called ‘tuberculids’ (erythema induratum, papulonecrotic tuberculid, and lichen scrofulosorum). In all cases, tissue biopsies for culture should be performed. Often in the later conditions, cultures and PCR studies fail to detect mycobacteria, but anti-TB treatment is still indicated. Despite Finsen being awarded the Nobel Prize for his invention of light therapy for cutaneous TB, there is currently no role for light therapy in the management of cutaneous TB and the cornerstone for therapy remains modern anti-TB drugs. All patients with cutaneous TB should receive multidrug therapy as recommended in their community for active TB. Duration of therapy should be at least 6 months. Single-drug treatments and shorter courses are not recommended. There is no special protocol for the treatment of cutaneous TB. Treatment of patients should be according to standard protocols as defined by the WHO or relevant national TB control programmes. The cost of treatment for TB may be paid for by local health departments, and protocols may vary from community to community, depending on the status of drug resistance in that community at that time. The most appropriate treatment protocol for a particular patient should therefore be determined by the clinician in accordance with official guidelines at that particular time and in that particular region. If cultures grow M. tuberculosis, susceptibility studies should guide anti-TB treatment. Most cases of TB are a manifestation of systemic involvement. The bacillary load in cutaneous TB is less than that in pulmonary TB. Treatment regimens are similar to that of TB in general.68 Fixed dose combination treatment with four drugs for 2 months in the intensive phase and two drugs for 4 months in the continuation phase is the treatment of choice for adults and children over the age of 8 years. A response of skin lesions is usually witnessed within 6 weeks. If there is no visible response after 6 weeks, the patient should be re-evaluated. Careful inquiry about compliance is essential. Children with cutaneous TB are treated with isoniazid, rifampicin, and pyrazinamide for 2 months followed by isoniazid and rifampicin for 4 months (WHO Regimen III – see Chapter 61).69
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Box 47.1 Differential diagnoses of various types of cutaneous tuberculosis
Tuberculous chancre ○ Tularaemia ○ Sporotrichosis ○ Cat scratch fever ○ Mycobacterium marinum infection ○ Syphilis. Tuberculosis verrucosa cutis ○ Blastomycosis ○ Chromoblastomycosis ○ Actinomycosis ○ Leishmaniasis ○ Tertiary syphilis ○ Hypertrophic lichen planus ○ Lichen simplex chronicus ○ Lesions caused by environmental (non-tuberculous) mycobacteria ○ Bromoderma ○ Hyperkeratotic lesions due to other mycobacteria. Lupus vulgaris ○ Lymphocytoma cutis ○ Spitz naevus ○ Lupus erythematosus ○ Leishmaniasis ○ Rosacea ○ Port-wine stain ○ Lesions caused by environmental (non-tuberculous) mycobacteria ○ Leprosy ○ Sarcoidosis ○ Psoriasis ○ Bowen’s disease ○ Lichen simplex chronicus ○ Wegener’s granulomatosis ○ Blastomycosis. Tuberculosis cutis orificialis ○ Secondary syphilis ○ Aphthous ulcers ○ Carcinoma ○ Herpes virus infection.
Miliary TB with skin involvement is treated with four drugs in the intensive phase and it is of utmost importance to ensure that the appropriate treatment protocol is initiated immediately (Chapter 61). A diagnosis of multidrug-resistant (MDR) TB should never be made clinically and laboratory confirmation of drug resistance is mandatory. It is difficult to demonstrate acid-fast bacilli in smears or biopsies, or to culture M. tuberculosis from cutaneous TB because most lesions are paucibacillary. A therapeutic trial of anti-TB treatment is frequently used to confirm the diagnosis in difficult cases. Previously there were no clear guidelines on when to expect a response or when to abandon a therapeutic trial. Ramam and co-workers70 showed that, when a therapeutic trial is undertaken in cutaneous TB, 6 weeks of therapy with four drugs appear adequate to prove or disprove the diagnosis. Therapeutic trials of antituberculosis treatment is not recommended in other types of tuberculosis and
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Scrofuloderma ○ Lesions caused by environmental (non-tuberculous) mycobacteria ○ Tertiary syphilis ○ Sporotrichosis ○ Actinomycosis ○ Acne conglobata ○ Hidradenitis suppurativa. Miliary cutaneous tuberculosis ○ Disseminated BCG infection ○ Bacterial folliculitis ○ Fungal folliculitis ○ Disseminated histoplasmosis ○ Papular and papulopustular syphilides. Tuberculous gumma (metastatic tuberculous abscess) ○ Panniculitis ○ Deep fungal infections ○ Tertiary syphilis ○ Hidradenitis suppurativa. Papulonecrotic tuberculid ○ Pityriasis lichenoides ○ Leucocytoclastic vasculitis ○ Papular urticaria ○ Secondary syphilis ○ Folliculitis ○ Perforating granuloma annulare. Erythema induratum of Bazin/nodular vasculitis ○ Other forms of panniculitis. Lichen scrofulosorum ○ Lichen nitidus ○ Keratosis pilaris ○ Papular or lichenoid sarcoidosis ○ Lichenoid secondary syphilis ○ Drug eruptions ○ Lichen planus. Nodular tuberculid ○ Insect bites ○ Evolving folliculitis ○ Evolving vasculitis ○ Dermal erythema multiforme.
should therefore not be done if any other systemic form of tuberculosis co-exists.
CONCLUSION Cutaneous manifestations of TB are relatively common in countries with a high prevalence of TB and may be the presenting clinical manifestation of the disease. Underlying systemic TB is often subtle and may be difficult to demonstrate. It is therefore of great importance that clinicians are familiar with the clinicopathological spectrum of cutaneous TB and that they maintain a high index of suspicion for underlying TB in patients with skin lesions as described in this chapter. A pragmatic approach to the diagnosis and management of cutaneous TB as outlined in the relevant table should facilitate and simplify optimal clinical care of patients.
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Dermatological manifestations of tuberculosis in adults and children
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