Tuberculosis
Salient features
|
· Infection
with Mycobacterium tuberculosis or other very closely related strains, as
well as the inflammatory reaction of the host define the disease
(tuberculosis, or TB). · One-third
of the world's population is infected with TB. · TB
is the main cause of death of patients infected with human immunodeficiency
virus. · TB
usually affects the lung, but virtually all other organ systems may be
involved. · TB
of the skin is a relatively rare manifestation with a wide spectrum of
clinical findings depending on the source of infection and the immune status
of the host. · Diagnosis
is based on clinical manifestations, histopathologic analysis, and
demonstration of the relevant Mycobacteria in tissue or in culture and host
reaction to M. tuberculosis antigen. · Treatment
is with standard multidrug regimens; cases of multidrug-resistant (MDR) TB or
extensively multidrug-resistant (XDR) TB require special attention. · Course
and prognosis depend on the immune status of the host. Treatment is curative
except for patients with a severely compromised immune system. |
Epidemiology
One-third of the world's population is infected with TB. M.
tuberculosis is not particularly virulent, as only 5% to 10% of infections
lead to clinical disease. HIV-infected individuals and those receiving
immunosuppressive therapies (especially TNF-α
inhibitors) are at particular risk for the development and reactivation of TB.
TB is the main cause of death of patients infected with human immunodeficiency
virus.
Cutaneous TB incidence parallels that
of pulmonary TB and developing countries still account for the majority of
cases in the world. The emergence of resistant strains and the AIDS epidemic
have led to an increase in all forms of TB.
Cutaneous TB is an uncommon form of
tuberculous infection, with less than 2% of cases of TB having skin lesions,
even in highly endemic areas. In countries like India, while great progress has
been made, TB is still very, very common, with 1.8 million new cases diagnosed
every year, or 2 new cases per 1000 population per year. Infection rates are
particularly high in India among healthcare workers; there are 17 new cases of
TB for every 1000 medical residents per year.
The two most frequent forms of skin tuberculosis are
lupus vulgaris (LV) and scrofuloderma. In the tropics, LV is rare, whereas
scrofuloderma and verrucous lesions predominate. LV is more than twice more
common in women than in men, whereas tuberculosis verrucosa cutis is more often
found in men. Generalized miliary tuberculosis is seen in infants (and adults
with severe immunosuppression or AIDS), as is primary inoculation tuberculosis.
Scrofuloderma usually occurs in adolescents and the elderly, whereas LV may
affect all age groups.
The Mycobacterium
M.
tuberculosis is a slender, non-motile, aerobic, non-spore-forming,
filamentous rod. It is an acid- and alcohol-fast bacillus that has a waxy
coating with a high lipid content, which makes it resistant to degradation
after phagocytosis.
Mycobacteria multiply intracellularly, and are initially
found in large numbers in the tissue.
In LV, the bacteria often have virulence as low as that
of the BCG. Large number of bacteria can be found in the lesions of a primary
chancre or of acute miliary tuberculosis; in the other forms, their number in
the lesions is so small that it may be difficult to find them.
The Host
The human species is quite susceptible to
infection by M. tuberculosis, with big differences among populations and
individuals. Populations that have been in long-standing contact with
tuberculosis are, in general, less susceptible than those who have come into
contact with Mycobacteria more recently, presumably reflecting widespread
immunity from subclinical infection. Age, state of health, environmental
factors, and particularly the immune system are of importance. Overcrowding, low socio‐economic status and poor living conditions are all
predisposing factors.
Classification
Clinical spectrum of cutaneous tuberculosis
The wide clinical spectrum of
cutaneous tuberculosis is dependent on the route of infection (endogenous or
exogenous), the immune status of the patient and whether or not there has been
previous sensitization with tuberculosis.
Primary inoculation of the skin,
usually following trauma, produces a tuberculous chancre in the non‐immune host, whereas the so‐called tuberculosis verrucosa cutis
occurs in primary infection in the immune host. Lupus vulgaris occurs mainly
through haematogenous, lymphatic or contiguous spread but can occur following
inoculation. Scrofuloderma results from contiguous extension of the skin
overlying tuberculosis in a deeper structure, most commonly lymphadenitis, bone
or joint disease, or epididymitis. Metastatic tuberculous abscesses
(tuberculous gumma) can occur due to haematogenous spread from a primary focus.
This usually occurs when host resistance is suppressed. Orificial, perioral or
perianal tuberculosis can occur following autoinoculation of mycobacteria.
The tuberculids are thought to be
the result of immunological reactions to haematogenously spread antigenic
components of M. tuberculosis, usually occurring in individuals with
high levels of immunity, with an extracutaneous source of M. tuberculosis.
M. tuberculosis complex DNA has been identified in some instances by PCR.
There are three main forms: lichen scrofulosorum, papulonecrotic tuberculid and
erythema induratum of Bazin.
More
recently, it has been suggested that a useful concept is the mycobacterial load
and that tuberculosis can be classified into multibacillary forms where there
are abundant mycobacteria (e.g. scrofuloderma, tuberculous chancre, and acute miliary
tuberculosis) and paucibacillary forms where mycobacteria are difficult to
isolate (e.g. lupus vulgaris, tuberculosis verrucosa cutis). In this
classification the tuberculids would sit at the extreme end of the
paucibacillary spectrum.
(A)
Classification of cutaneous tuberculosis
|
Host
immunity |
Method of inoculation |
Disease |
|
Multibacillary forms |
||
|
Naive host |
Direct
inoculation |
Tuberculous
chancre (primary inoculation |
|
Low |
Contiguous
spread |
Scrofuloderma |
|
Low |
Autoinoculation |
Orificial
tuberculosis |
|
Low |
Haematogenous
spread |
Acute miliary
cutaneous |
|
Low |
Haematogenous
spread |
Tuberculous gumma
(abscess) |
|
Paucibacillary forms |
||
|
High |
Direct
inoculation |
Warty
tuberculosis (verrucosa cutis) |
|
High |
Direct
inoculation |
Lupus
vulgaris (some) |
|
High |
Haematogenous
spread |
Lupus
vulgaris |
|
High |
?Haematogenous
spread |
Erythema
induratum (Bazin's) Papulonecrotic tuberculid Lichen scrofulosorum Tuberculids |
(B)
Classification of Cutaneous Tuberculosis
|
Host Immune Status |
Clinical Disease |
|
|
Exogenous infection |
Naive Immune |
Primary inoculation tuberculosis Tuberculosis verrucosa cutis |
|
Endogenous spread |
High Low |
Lupus vulgaris Scrofuloderma Acute miliary tuberculosis Orificial tuberculosis Metastatic tuberculous abscess (tuberculous gumma) |
|
Tuberculosis due to Bacille Calmette-Guérin |
Naive |
Normal primary complex-like reaction Perforating regional adenitis Post vaccination lupus vulgaris |
|
Tuberculids |
Not clear |
Tuberculids: Lichen scrofulosorum Papulonecrotic tuberculid Facultative tuberculids: Nodular vasculitis Erythema nodosum |
Pathogenesis
Mycobacterium
tuberculosis and M. bovis and
occasionally BCG, an attenuated form of M. bovis, are pathogenic to
humans. The majority of human disease is due to M. tuberculosis, M. bovis
being found in only 1–1.5% of isolates.
M.
tuberculosis
disseminates primarily via inhalation of aerosolized droplets from individuals
with active disease, resulting in pulmonary infection. M. bovis may also
penetrate the gastro‐intestinal
mucosa and lymphatic tissue of the oro‐pharynx when ingested in milk. Direct
inoculation of the skin by M. tuberculosis complex also occurs
particularly if there is any defect in the skin barrier. Intact skin provides
an effective protective barrier against invasion of the organism, but a break
in the mucocutaneous barrier can facilitate its entrance. Untreated infected individuals who do not have underlying
medical problems have a 5% to 10% lifetime risk of progression to active TB;
this risk increases substantially with immunosuppression, e.g. due to HIV
infection or treatment with medications such as TNF inhibitors.
Survival of Mycobacterium
species in aerosols generated from human saliva is usually less than an hour,
indicating that close and prolonged contact is required for transmission of
infection.
The
sensitization status of the host to mycobacterial antigens (e.g. previously
infected versus never exposed), the degree of cell-mediated immunity of the
host, the route of infection, and the pathogenicity of the infective strain of
mycobacteria determine the resulting infection. In immunocompromised hosts,
cell-mediated immunity is impaired; as a consequence, there may be reactivation
of quiescent disease.
Histopathology
The histopathological
picture depends on the immune status of the host. In patients who are exposed
for the first time, there is diffuse inflammation initially with neutrophils
and later granuloma appears after 3–6
weeks of
infection. In those with immunity, the characteristic lesion is tubercle: an
accumulation of epithelioid histocytes with langhans-type giant cells among
them surrounded by a rim of lymphocytes and macrophages. The center of the tubercle undergoes caseation necrosis and
sometimes calcifies. The necrotic material appear cheesy, leading to the term
caseation necrosis.
Diagnostic
tests for cutaneous tuberculosis
The diagnosis of skin tuberculosis
may be suggested by clinical features and typical histological findings but the
only absolute criterion is the demonstration of M. tuberculosis in
either tissue culture from skin biopsy or cytological smear, or the
demonstration of mycobacterial DNA by PCR.
Other
indications toward the diagnosis, which are by themselves unreliable, include
the following:
1.
The presence of active, proven
tuberculosis elsewhere in the body.
2.
Direct microscopy identification of
acid‐fast bacilli in
the lesion itself (skin tissue sections) using Ziehl-Neelsen stain.
3.
A positive reaction to tuberculin –
a strongly positive reaction of >15 mm in diameter may be considered of
diagnostic value.
4.
Positive IFN‐γ release assay.
5.
The effect of specific therapy – in
areas of high tuberculous prevalence a therapeutic trial of antituberculous
therapy should be considered.
Culture is the most
important laboratory test due to its high sensitivity and specificity.
Mycobacterial tissue culture takes 4-6 weeks and then allows determination of
antibiotic sensitivities. A positive culture result not only confirms skin
tuberculosis, but allows detection of drug resistance.
In tuberculin skin
test, an antigen extract from M. tuberculosis (also known as standardized
purified protein derivative, PPD-S).It is injected intracutaneouly (Mantaux
test) and a reaction is monitored 48-72 hours later. A person who has never
been exposed to M. tuberculosis fails to react; this is known as anergy.
Someone who has been exposed reacts positively with an indurated papule. The loss
of this response (negative anergy) suggests immunosuppression and a poor
prognosis. Patients who over-react (hyperanergy) to the Mantaux skin test are
most likely to develop tuberculids. Tuberculin sensitivity usually develops
2–10 weeks after infection and persists throughout life.
In addition to the
use of tuberculin skin tests, M. tuberculosis infection can be diagnosed
with IFN-γ release assays (IGRA) (e.g. QuantiFERON®
TB Gold). This assay determines whether exposure to recombinant peptides from M.
tuberculosis (ESAT-6 + culture filtrate protein [CFP]-10) stimulates IFN-γ production by T cells within patient blood samples.
The US Centers for Disease Control and Prevention (CDC) guidelines state that
an IFN-γ release assay may be used in place of a
tuberculin skin test in all situations where the latter would be employed.
Advantages and disadvantages of these methods of TB detection as well as
special situations where one type of test would be preferred are listed below:
|
Tuberculin
skin test |
IFN-γ release assays |
|
|
Advantages |
Does not require a laboratory |
Requires a single patient visit |
|
Disadvantages |
Requires two patient visits |
Requires laboratory processing Relatively high cost |
|
Situations where preferable |
Children <5 years of age |
Patient unable to return for a second visit (e.g.
homeless persons, drug users) |
QuantiFERON®-TB Gold (QFT-G) Test
In 2005, the FDA approved QFT-G as an in vitro diagnostic
aid. In this test, blood samples are mixed with antigens. For QFT-G, the
antigens include mixtures of synthetic peptides representing two M.
tuberculosis proteins: (1) ESAT-6 and (2) CFP-10.
After incubation of the blood with antigens for 16–24 hours, the amount of
interferon-γ (IFN-γ) is measured. These antigens are considered to be more
specific for M. tuberculosis than tuberculin.
If the patient is infected with M. tuberculosis, their T
cells will release IFN-γ in response to contact with the TB antigens. The QFT-G
results are based on the amount of IFN-γ that is released in response to the
antigens. Although more sensitive than the tuberculin skin test,
the QFT-G may be negative in patients with early active tuberculosis and
indeterminate results are more common in immunocompromised individuals and
young children. Another similar assay, the T-SPOT®.TB test, measures the number
of IFN-γ-producing T cells. QFT-G testing is indicated for diagnosing infection
with M. tuberculosis, including both TB disease and latent TB infection.
Clinical Features
Cutaneous TB
has a wide variety of clinical presentations. Lesions can be due to direct
inoculation of M. tuberculosis from an exogenous source, e.g.
tuberculous chancre, TB verrucosa cutis and, occasionally, lupus vulgaris. Skin
involvement due to endogenous infection may appear as scrofuloderma, acute
miliary TB, a tuberculous gumma, orificial TB and lupus vulgaris. In addition,
immune reaction to M. tuberculosis can have several cutaneous
manifestations, which are called tuberculids.
Summary of clinical features
Tuberculous chancre
Incidence: Rare; 1–2% of cutaneous tuberculosis
Transmission: Inoculation into skin and/or mucosa
of previously uninfected person, i.e. with no specific immunity
Tuberculin skin test: Early: negative; Later:
positive
Diagnosis: Histology and
culture; PCR; IGRA*
Tuberculosis verrucosa cutis
Incidence: Most common form of cutaneous tuberculosis
Transmission: Inoculation into skin and/or mucosa of
previously infected person with moderate or high immunity
Tuberculin skin test: Positive
Diagnosis:
Culture; PCR; IGRA
Scrofuloderma
Incidence: Common in immigrants from developing countries
Transmission: Contiguous involvement of skin overlying a
focus of tuberculosis, usually in lymph node or bone. Also reported after BCG
vaccination
Tuberculin skin test: Usually positive
Diagnosis:
Culture; PCR; IGRA
Orificial tuberculosis
Incidence: Rare
Transmission: Autoinoculation of mucosa
or skin adjacent to a natural orifice draining an active internal tuberculous
infection
Tuberculin skin test:
Variable, often negative
Diagnosis: Histology and culture; PCR;
Presence of another focus of TB; IGRA*
Lupus vulgaris
Incidence: Low: 10–15% of cutaneous tuberculosis;
women affected 2–3 times more often than men
Transmission: Direct extension;
hematogenous or lymphatic spread from a tuberculous focus; reinfection; BCG
vaccination
Tuberculin skin test:Usually
positive
Diagnosis:
Histology and culture; PCR; IGRA
Acute cutaneous military tuberculosis
Incidence: Rare; infants and young children,
seldom adolescents or adults
Transmission: Hematogenous dissemination
from primary lung focus in patient with low immunity; may follow viral
infection
Tuberculin skin test:Usually
negative
Diagnosis:
Smear; histology and culture; PCR; Presence of another focus of TB; IGRA*
Metastatic tuberculous abscess
Incidence: Children with low socioeconomic status
or immunocompromised hosts
Transmission: Acute hematogenous
dissemination from a primary focus during periods of bacillemia and lowered
resistance
Tuberculin skin test: Usually
negative
Diagnosis:
Culture and histology; PC; IGRA*
* May have an
indeterminate result early in the disease course or in immunocompromised
patients.
Primary inoculation-PIT
Introduction
Tuberculous chancre and affected regional
lymph nodes constitute the tuberculous primary complex in the skin. Primary inoculation tuberculosis develops as a result of
inoculation of mycobacteria into the skin or mucosa of an individual not previously
infected or having no natural or artificially acquired immunity to
tuberculosis. Some form of injury is mandatory for the initiation of the
infection, as the tubercle bacillus cannot penetrate the normal intact skin or
mucosal barrier. Thus the bacillus enters the skin through abrasions and minor
injuries, usually on the face or limbs and commonly in children. Oral lesions may be
caused by bovine bacilli in non pasteurized milk and occur after mucosal trauma
or tooth extraction. Primary inoculation tuberculosis is initially
multibacillary, but becomes paucibacillary as immunity develops.
Epidemiology
Incidence
and prevalence
This
is believed to be an uncommon form of skin tuberculosis.
Age
It
commonly affects children.
Predisposing
factors
Children
are most at risk, particularly those who have not received BCG vaccination.
Laboratory and healthcare workers may also be at risk.
Pathology
The
early changes are those of acute neutrophilic inflammation with necrosis
occurring in both the skin and affected lymph nodes. Numerous bacilli are
present. After 3–6 weeks, the infiltrate becomes more granulomatous and
caseation appears, coinciding with the disappearance of the bacilli.
Clinical
features
Initially a painless, firm, reddish-brown papulonodule develops
2 to 4 weeks after the inoculation of M. tuberculosis into the skin. It
slowly enlarges, eventually eroding to form a sharply demarcated painless ulcer. The ulcer is
shallow with a granular or hemorrhagic base studded with miliary abscesses or
covered by necrotic tissue. The ragged edges are undermined and of a
reddish-blue hue. As the lesions grow older, they become more indurated, with
thick adherent crusts. Sites of predilection are the face, including the
conjunctivae and oral cavity, as well as the hands and lower extremities. Frequently
there is spread to draining lymphatics and regional
lymphadenopathy develops 3–8 weeks after the infection and may rarely
be the only clinical finding; the combination of the latter with a tuberculous
chancre is analogous to the Ghon complex in the lung.
Diagnosis
Any painless, non‐healing ulcer with unilateral regional lymphadenopathy in a
child should arouse suspicion. Acid-fast organisms are found in the primary
ulcer and draining nodes in the initial stages of the disease. The diagnosis is
confirmed by bacterial culture. The PPD reaction is negative initially and
later converts to positive.
Disease
course and prognosis
The skin lesion usually heals
spontaneously within 3 to 12 monthsleaving an atrophic scar. The tuberculous chancre may occasionally evolve into tuberculosis verrucosa cutis or lupus vulgaris. The enlarged draining lymph nodes usually subside slowly,
often calcifying; less often, cold abscesses and sinuses develop producing
scrofuloderma.
Warty (tuberculosis verrucosa cutis)-TVC
Etiology and
Pathogenesis
Tuberculosis verrucosa cutis is a paucibacillary disorder
caused by exogenous reinfection (inoculation) of M. tuberculosis into the skin through a minor
injury
in previously infected or
sensitized individuals having
a high degree of immunity.
This
commonly occurs by accidental inoculation from extraneous sources particularly
in healthcare workers. Persons walking barefoot where the organism is present
may similarly become infected.
Epidemiology
Worldwide
the incidence of tuberculosis verrucosa cutis appears to be commonest in Asia.
Histopathology
The most prominent histopathologic features are
pseudoepitheliomatous hyperplasia with marked hyperkeratosis, a dense
inflammatory infiltrate, and microabscesses in the upper dermis or within the pseudoepitheliomatous
rete pegs. Epithelioid cells and giant cells are found in the upper and middle
dermis. Typical tubercles are uncommon, and the infiltrate may be nonspecific. Ziehl-
Neelsen staining is usually negative.
Clinical
features
The lesion begins as a small, asymptomatic, firm papule
with a violaceous inflammatory halo. The overlying epidermis becomes
hyperkeratotic, resembling an inflamed wart. Slow growth and peripheral
expansion lead to the development of a firm reddish-brown verrucous plaque with
an irregular border. The center of the
lesion may become softens, with pus and keratinaceous debris expressed by
slight pressure. The lesion usually is solitary, but multiple lesions may
occur. Regional lymph nodes are not affected. Lesions progress slowly and, if
untreated, persist for many years. Spontaneous involution eventually occurs,
leaving an atrophic scar. Lesions occur on those areas exposed to trauma such
as dorsum of the fingers and hands in adults and ankles, knees and buttocks in
children.
Investigations
Culture of the skin lesions is positive in about half the
cases.
PCR
may be helpful if positive but is often negative in paucibacillary forms of
cutaneous tuberculosis.
Lupus vulgaris-LV
Definition
This is a chronic, progressive,
paucibacillary form of cutaneous tuberculosis, occurring in a previously
sensitized individual with a high degree of immunity to tuberculin.
Lupus
vulgaris is the most common form of cutaneous tuberculosis in adults. A characteristic
lesion is a slowly enlarging plaque with an elevated border and central atrophy and scarring.
Epidemiology
Females appear to be affected two to three
times as often as males; all age groups are affected equally.
Pathophysiology
LV is a post primary, paucibacillary form of
tuberculosis caused by hematogenous, lymphatic, or contiguous spread from
elsewhere in the body. It can also arise after exogenous
inoculation or as a complication of BCG vaccination. Those on the face are
usually thought to be due to haematogenous spread, while those located on the
extremities are more likely to be due to exogenous inoculation.
Pathology
The hallmark is caseating tuberculous granuloma. The epidermis is usually atrophic,
although acanthosis with hyperkeratosis and occasionally pseudoepitheliomatous
hyperplasia can occur. The microscopic
tubercles are smaller than the clinically visible lupus nodule, which consists
of a conglomeration of tubercles. Acid-fast bacilli are usually not found.
Clinical
features
Lesions
are usually solitary, but two or more sites may be involved simultaneously. In
patients with active pulmonary tuberculosis, multiple foci may develop. In
approximately 90% of patients, the head and neck are involved. LV usually starts
on the nose, cheek, rim of the ear, or scalp and slowly extends onto adjacent
regions. Next in frequency are extensor
surface of the limbs, lateral surface of the buttocks and breasts. In children
the lesions are often on the lower limbs and buttocks; they usually occur by
reinoculation and may relate to playing without clothing or shoes.
The
initial lesion is a brownish-red, soft or friable papule with a smooth or
hyperkeratotic surface. On diascopy, the diagnostic pinhead
sized ‘apple jelly’ nodules, called lupus nodules, are seen in the dermis,
floating like a piece of sago in topoica pudding. Progression is characterized by
elevation, a deeper brownish color, and formation of a plaque. Involution
in one area with scarring and atrophy and expansion in another
area often results in a gyrate outline border.
This can
lead to substantial tissue destruction over a period of years.
Another
clinical diagnostic technique is the use of a thin, blunt or rounded probe.
When gentle pressure is applied in the center of the lesion, the probe
penetrates the skin; when it is withdrawn, a drop of blood appears.
There
are five clinical patterns, depending on the local tissue response to the
infection.
1.
Plaque
form. Flat plaques are found with
irregular or serpiginous edge. The surface of the lesion 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.
2.
Ulcerative
and mutilating forms. Scarring and
ulceration predominate. Crusts form over areas of necrosis. The deep tissues
and cartilage are invaded and contractures and deformities occur. In milder
forms, keratotic plugs overlying pinpoint ulcers are associated with slow scar
formation.
3.
Vegetating
form. This is characterized by 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 ensue.
4.
Tumor‐like forms. The hypertrophic form presents either as soft tumor‐like nodules or as epithelial
hyperplasia with the production of hyperkeratotic masses. In the ‘myxomatous’
form, huge soft tumors occur predominantly on the ear lobes, which become
grossly enlarged. Lymphedema and vascular dilatation are sometimes marked.
5.
Papular
and nodular forms. After a transient impairment of
immunity, particularly after measles (thus the term lupus post exanthematicus),
multiple disseminated lesions may arise simultaneously in different regions of
the body as a consequence of hematogenous spread from a latent tuberculous
focus. During and after the eruption, a previously positive tuberculin reaction
may become negative but will usually revert to positive as the general
condition of the patient improves.
Mucosal
involvement
The
nasal, buccal or conjunctival mucosa may become involved, either primarily, or
by spread from a contiguous skin lesion. Nasal lesions start as nodules, which
bleed easily and then ulcerate, leading sometimes to cartilage destruction. Dry rhinitis is often
the only symptom of early nasal LV. Granulating, vegetating or ulcerating lesions
of the buccal mucosa, palate, gingiva or oro‐pharynx may occur by direct extension or by lymphatic spread
from nasal lesions. These can produce stenosis of the larynx and scarring
deformities of the soft palate.
Complications
and co‐morbidities
Scarring, contractures and tissue
destruction are prominent features. The scars are usually thin, white and
smooth, but are unstable and may break down or become keloidal. Contraction may
lead to ectropion or microstomia, which may require plastic surgery. Active
lupus vulgaris frequently reappears in scar tissue.
Malignant changes are well known to
arise in longstanding lupus vulgaris. Squamous cell carcinoma is the most
common tumor, known as lupus carcinoma, and usually takes about 25–30 years to
develop with a high
risk of metastases and normally occurs in patients in their
fourth and fifth decades. Basal cell carcinoma also occurs.
Disease
course and prognosis
LV is a very long-term disorder and without
therapy progresses over many years to functional impairment and disfiguration. With appropriate treatment there is often a clinical
response as early as 5 weeks and usually marked improvement by 10 weeks.
Failure to respond within 4–6 weeks may suggest an alternative diagnosis.
In 40% of patients, there is associated tuberculous
lymphadenitis, and 10%–20% have active pulmonary tuberculosis or tuberculosis
of the bones and joints. Pulmonary tuberculosis is 4–10 times more frequent in
patients with LV than in the general population.
Diagnosis
Typical LV plaques may be recognized by the softness of
the lesions, brownish-red color, and slow evolution. The apple jelly nodules
revealed by diascopy are highly characteristic; finding them may be decisive,
especially in ulcerated, crusted, or hyperkeratotic lesions. Stains for acid‐fast
bacilli are usually negative. Bacterial culture results are positive in 50% cases and if
negative, the clinical diagnosis can be confirmed by
positive PCR. The tuberculin
test is strongly positive and IFN‐γ
assays may also be helpful.
Scrofuloderma-SD
Definition
Scrofuloderma is subcutaneous tuberculosis leading to
cold abscess formation and a secondary breakdown of the overlying skin. It may
be either multibacillary or paucibacillary.
Scrofuloderma represents contiguous involvement of the
skin overlying another site of infection (e.g., tuberculous lymphadenitis,
tuberculosis of bones and joints, or tuberculous epididymitis).
Epidemiology
Incidence
and prevalence
Worldwide,
it is the commonest form of cutaneous tuberculosis.
Age
It is most
common in children, adolescents, and the aged.
Sex
Males
were affected 1.5 times more than females.
Histopathology
Massive necrosis and abscess formation in the center of
the lesion are nonspecific. However, the periphery of the abscesses or the
margins of the sinuses contain tuberculoid granulomas.
Clinical
features
Scrofuloderma most often occurs in the parotidal, submandibular,
and supraclavicular regions and may be bilateral. It begins as a firm, asymptomatic,
bluish red, freely movable,deep-seated,
subcutaneous nodule that has accumulated inflammatory material and necrotic
tissue, best characterized as a “cold abscess”.
As the lesion enlarges, the suppurative
nodule softens and become fluctuant and invades the overlying skin and
break down, forming sinus tracts and ulcerswith extrusion of purulent and
caseous material. The ulcers are linear
or serpiginous with undermined, inverted, bluish edges and soft, granulating
floors. Multiple ulcers can appear. Sinusoidal tracts undermine the skin. After healing, keloids and retracted tethered scars develop
at the sites of infection. Tuberculin sensitivity is usually pronounced.
Disease
course and prognosis
Spontaneous healing does occur, but the course is very
protracted, and it may be years before lesions have been completely replaced by
scar tissue. Presence of the typical cribriform scars permits a correct
diagnosis, even after the process has become quiescent. LV may develop at or
near the site of scrofuloderma.
Investigations
If there is an underlying tuberculous lymphadenitis or
bone and joint disease, the diagnosis usually presents no difficulty. A 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, the latter can be used as a first line investigation. Positive
mycobacterial culture confirms
the diagnosis.
Orificial tuberculosis-OT
Introduction
Orificial tuberculosis is a rare multibacillary
form of tuberculosis of the mucous membranes and the skin adjoining orifices that is caused by
autoinoculation of mycobacteria from progressive tuberculosis of internal
organs.
Affected individuals typically have advanced
pulmonary, intestinal, or, rarely, genitourinary tuberculosis in the setting of impaired cell-mediated immunity.
Mycobacteria shed from these foci in large numbers are inoculated into the
mucous membranes.
Epidemiology
Age
It
usually affects middle‐aged
and elderly males.
Pathology
The
histopathological changes are often of a non‐specific inflammatory type. In most cases a tuberculoid
infiltrate with pronounced necrosis is found in the deep dermis. Tubercle
bacilli are numerous.
Clinical
features
History
Patients
give a history of painful ulceration around orifices and may have
constitutional symptoms such as fever, malaise, weight loss and night sweats.
Presentation
The affected
patient is usually a severely ill adult with advanced visceral tuberculosis who
may have failing resistance to the disease. The most common
location is the mouth, especially the tongue, particularly the
tip and the lateral margins, but the soft and hard palates are also common
sites. In advanced cases, the lips are involved, and the oral condition often
represents an extension of ulcerative tuberculosis of the pharynx and larynx. In
patients with intestinal tuberculosis, lesions develop around the anus, and in
females with active genitourinary disease, the vulva is involved.
The initial lesions are edematous red nodules that rapidly break down to
form a
soft ulcer with a typical punched-out appearance, undermined bluish edges,
and circular or irregular border. The ulcer floor often exhibits multiple
yellowish tubercles and bleeds easily. The ulcers are painful, recalcitrant to
treatment, and do not tend to heal spontaneously. The surrounding mucosa is
edematous and inflamed. Lesions may be single or multiple. The severe pain may
interfere with eating, defecating or urinating, if spreading from renal
tuberculosis affects the urethra.
Investigations
Histology
from a skin biopsy sample, and occasionally smear cytology from the base of a
purulent ulcer, will usually show multiple acid‐fast bacilli. Cultures of tissue are normally positive
within 6 days. If available, PCR may give a result within 24 h. As patients
often have severely impaired cell‐mediated immunity, the tuberculin test is often negative.
Course
Orificial tuberculosis is a symptom of advanced internal
disease and usually portends a fatal outcome.
Acute cutaneous military tuberculosis-AMT
Definition
Acute
miliary tuberculosis is
an extremely rare multibacillary form caused by the haematogenous spread of tubercle bacilli into the skin
from advanced pulmonary or meningeal tuberculosis.
It
affects infants and young children or immunosuppressed patients. Most reported
instance of cutaneous TB seen in patients with AIDS is of this type.
Pathology
Histology
shows necrotizing tuberculous granulomas with multiple acid‐fast bacilli.
Clinical
features
The initial
lesions of miliary tuberculosis are pinhead-sized, bluish-red papules
capped by minute vesicles in a patient who is obviously ill. The lesions can
occur all over the body, particularly on the trunk. The vesicles develop a tiny
central umbilication followed by the formation of crusts. When the papules
heal, they leave a residual white scar with a brownish rim.
Disease
course and prognosis
The
prognosis is poor, but the patients respond to treatment.
Investigations
The
development of an unusual exanthematic rash in an ill person with known
tuberculosis suggests the diagnosis, which should be confirmed by skin biopsy.
The tuberculin test is negative.
Metastatic tuberculous abscess (MTA)
Definition
Metastatic tuberculous abscesses or
tuberculous gummata result from the haematogenous dissemination of mycobacteria
from a primary focus during periods of lowered resistance, particularly in
malnourished children or in immunodeficient adults.
Clinical Findings
MTA present as
single or multiple subcutaneous abscesses andmay invade the
overlying skin and break down, forming sinuses and ulcers. Unlike scrofuloderma, there is no
involvement of underlying tissue. The extremities are more often affected than
the trunk. Tuberculin
sensitivity is usually lower than in other forms of cutaneous tuberculosis and
may be absent in severely ill patients.
Pathology
As in scrofuloderma, massive necrosis and
abscess formation are found. Acid-fast stains usually reveal copious amounts of Mycobacteria.
Investigations
The
diagnosis is confirmed by culture. The patient should be screened for an
underlying focus of tuberculosis and causes of immunosupression. The tuberculin
test is usually negative.
TUBERCULIDS
The
tuberculids represent a group of disorders that classically were associated
with a focus of internal TB. They are considered to be 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. Often beginning as an immune complex-mediated reaction, they evolve
into a granulomatous inflammatory response. The diagnostic criteria include
tuberculoid histology on skin biopsy, a strongly positive Mantoux reaction, and
absence of M. tuberculosis in the smear and negative culture and resolution of
the skin lesions with antituberculous therapy.
Classification
True tuberculids can be grouped as follows:
Micropapular: lichen scrofulosorum.
Papular: papulonecrotic tuberculid.
Nodular: erythema induratum of Bazin or nodular
tuberculid.
Lichen scrofulosorum
Epidemiology
Age
Lichen scrofulosorum appears to be commonest in children
and adolescents, 84% of patients are less than 15 years of age.
Pathogenesis
Lichen scrofulosorum is an uncommon lichenoid eruption
ascribed to hematogenous spread of Mycobacteria in an individual strongly
sensitive to M. tuberculosis. Usually associated with chronic tuberculosis of
the lymph nodes, bones, or pleura, it has also been observed after BCG
vaccination.
Pathology
Histologic examination demonstrates superficial
granulomas around hair follicles and sweat ducts, with little or no caseation
necrosis. Mycobacteria are not seen in the sections and cannot be cultured from
biopsy material;however, PCR testing has
demonstrated M. tuberculosis DNA within
lesions.
Clinical features
The eruption consists of firm, tiny follicular
flat-topped, closely grouped yellowish or pink papules, usually with a
keratotic cap, often closely resemble lichen nitidus. These
asymptomatic papules are grouped in clusters, predominantly on the trunk,
and lesions may coalesce to form rough, discoid plaques. Lesions may persist
for months and then disappear without scarring.
Although it is seen in all age groups, children with nodal or skeletal TB are
most frequently affected.
Disease course and
prognosis
With specific antituberculous therapy, the lesions
usually clear within 4 weeks.
Papulonecrotic tuberculid
Papulonecrotic tuberculid is a symmetric eruption of
necrotizing papules, appearing in crops and healing with scar formation.
Epidemiology
Incidence
Papulonecrotic tuberculid is uncommon and accounts for
approximately 4% of patients with cutaneous tuberculosis.
Age
It usually affects young adults and occasionally
children, over 65% of patients developed the lesions before the age of 30
years.
Etiology and
Pathogenesis
As a rule, bacteria cannot be demonstrated in lesions. In
most cases, the tuberculin test shows a positive reaction, and associated
pulmonary or extrapulmonary tuberculosis is common. LV has been reported to
evolve with papulonecrotic tuberculid.
Although papulonecrotic tuberculid is classified as an id
reaction and therefore, by definition, is not due to direct involvement of the
skin by the organism, some of the lesions have been positive on culture. It
seems most likely that papulonecrotic tuberculid is a reaction to particulate
tuberculous antigen and, in some cases, to living organisms as well.
Pathology
Characteristically, a wedge-shaped necrotic area in the
upper dermis extends into the epidermis. The inflammatory infiltrate
surrounding this necrotic area may be granulomatous, but classic tubercles are
not found. Involvement of the blood vessels is a cardinal feature and consists
of an obliterative and sometimes granulomatous vasculitis leading to thrombosis
and complete occlusion of the vascular channels.
PCR for mycobacterial DNA and the tuberculin
test are positive.
Clinical features
Sites of predilection are the extensor aspects of the
extremities, buttocks, and lower trunk, but the eruption may become widespread.
Distribution is symmetric, and consists of disseminated crops of dusky red
papule that develops central necrosis and an adherent crust over a crater-like
ulcer. Usually there is spontaneous healing of
individual lesions, which leaves pitted scars. Crops of new lesions may
continue over months or years. Scars are typically present together with fresh
lesions. The eruption is asymptomatic and is more common in winter, improving
in the summer.
Disease course and
prognosis
With specific antituberculous therapy, the lesions
usually clear within 4 weeks.
Erythema Induratum of Bazin/Nodular
Vasculitis
Introduction
Erythema induratum of Bazin is the most commonly reported
form of tuberculid and represents a tuberculosis‐associated
lobular panniculitis. The term erythema induratum of Bazin is reserved for cases
related to M. tuberculosis. Nodular
Vasculitis is a similar condition without MTB association.
Both immune complex deposition, which may
play a role in the vasculitic component, and a delayed-type hypersensitivity
reaction to mycobacterial antigens, are thought to be involved in the
pathogenesis. Women are most commonly affected (80–90% of patients), with peaks
in incidence during early adolescence and around menopause, who
classically present with crops of small, tender and painful erythematous or
dusky nodules or deep‐seated plaques on the calves which may
ulcerate.
Predisposing factors
Past or active foci of tuberculosis are usually present
and the tuberculin test is usually positive.
Histopathology
·
Mostly
lobular or mixed lobular and septal panniculitis with vasculitis in 90%.
·
Extensive
necrosis of the adipocytes in the center of the fat lobule.
·
Variable
inflammatory infiltrate in the fat lobule: neutrophils in early lesions and
epithelioid histiocytes and multinucleated giant cells in fully developed
lesions.
·
Vasculitis
of the small veins and venules of the fat lobule.
Clinical features
EI/NV presents with recurrent erythematous to violaceous subcutaneous
nodules and plaques on both the lower legs that may be tender to pressure.
The plaques are usually indurated. Some
lesions may heal spontaneously without ulceration and scarring,
especially in the summer months. But the lesions often ulcerate, usually
centrally, and this may be precipitated by cold weather or venous stasis. The
ulcers are ragged, irregular and shallow, with a bluish edge. Surface
changes include crusting of the ulcers and a surrounding collarette of scale. The
lesions heal with atrophic, hyper pigmented scarring. The
posterior leg calf region is the most frequent location, but lesions may also
appear in the anterolateral areas of the legs, the feet, thighs, and rarely the
arms and face. EI lesions develop more frequently during winter, and EI is
commonly associated with obesity and venous insufficiency.
Disease course and
prognosis
Untreated, the disease course is chronic with recurrent
crops of new lesions sometimes over many years. Response to antituberculous
therapy may take between 1 and 6 months and resolution may be slow, even with
adequate therapy, particularly if there are associated erythrocyanotic
features.
Investigations
The diagnosis is made on characteristic clinical
morphology, a positive tuberculin test and circumstantial evidence of
tuberculosis elsewhere in the body, supplemented by histopathological findings.
Detection of M. tuberculosis DNA by PCR on the skin biopsy specimen may be
positive but a negative result does not exclude the diagnosis. Commercially
available IGRAs such as the QuantiFERON‐TB Gold test may be
helpful in diagnosis of latent tuberculosis. Although cases of active
tuberculosis are rare in erythema induratum, the patient should be fully
investigated for subclinical active tuberculosis infection. The diagnosis can
be confirmed by a good response to antituberculous therapy. In cases where the
diagnosis of tuberculosis seems unlikely, testing for chronic hepatitis C viral
infection and other infections including fungi and parasites, should be sought
and treated, if present.
Treatment
In patients with positive MTB
cultures, positive skin test or Quantiferon gold test for MTB, treatment with
triple agent antituberculosis therapy is indicated. Patients with hepatitis B
or C should receive appropriate intervention for that disorder. Other
infectious etiologies including fungi, parasites, and viruses should be sought
and treated, if present. Medications that may have incited EI should be
discontinued.
Anti-inflammatory
treatments that have been used in EI/NV not associated with MBT include super
saturated potassium iodide (SSKI), nonsteroidal anti-inflammatory agents
(NSAIDS), colchicine, antimalarials, corticosteroids, as well as bed
rest or leg elevation, and treatment of venous insufficiency with compression
and pentoxifylline. Other treatments that have been used include tetracycline and mycophenolate mofetil. If immunosuppressive agents are
used, continued monitoring for possible infectious etiology is recommended.
First line
Full course of specific antituberculous therapy should be
given according to current recommended guidelines for systemic tuberculosis.
Second line
In some patients simple measures such as bed rest, leg elevation, non‐steroidal
anti‐inflammatory
drugs and compression bandaging may be helpful. The patients should also try to
keep her legs warm, warm clothing, warm baths and adequate heating.
Algorithm for the management of cutaneous tuberculosis
TREATMENT
OF TUBERCULOSIS
Tuberculosis,
pulmonary or extrapulmonary, is an AIDS‐defining illness. HIV testing is recommended for all patients
diagnosed with TB, because they may require longer courses of therapy. In
addition, every effort should be made to culture the organism for sensitivity
testing, since MDR-TB is common in some communities. For all forms of cutaneous
TB, multidrug chemotherapy is recommended. Three- or four-drug regimens are
usually recommended for initial empiric treatment.
Virtually all forms of cutaneous TB
will have begun to respond to treatment by 6 weeks. Failure to respond within
this timeframe should result in reconsideration of the diagnosis, assessment
for compliance, and concern about drug resistance.
Drug therapy
Treatment of cutaneous tuberculosis
should follow the same drug regimen as that for systemic tuberculosis. ATT is not only effective
in individuals with active or latent infection but also prevents bacterial
resistance and reduces transmission of M. tuberculosis. The NICE 2011 guidelines recommend that the treatment of all
patients should be supervised by physicians with full training in the
management of tuberculosis and with direct working access to tuberculosis nurse
specialists or health visitors.
Patient non‐compliance is currently one of the
most important factors limiting successful treatment. Directly observed therapy
(DOT), where the ingestion of every drug dose is witnessed, has shown improved
cure rates in a number of countries.
DOT considered for those patients
having adverse factors. These include patients who are homeless, alcoholics or
drug abusers, drifters, seriously mentally ill patients, patients with multiple
drug resistances and those with a previous history of non‐compliance with antituberculous
medication. In DOT an intermittent regimen is often more convenient.
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CLASSES, ACTIVITIES
AND CROSS-RESISTANCES OF THE ANTITUBERCULOUS AGENTS |
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Agent |
Class of compound |
Spectrum of activity |
Cross-resistance to
other antituberculous agents |
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First-line agents |
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|
1.
Rifampin 2.
Isoniazid 3.
Pyrazinamide 4.
Ethambutol 5.
Rifapentine 6.
Rifabutin |
1.
Antibiotic 2.
Synthetic 3.
Synthetic 4.
Synthetic 5.
Antibiotic 6.
Antibiotic |
1.
Broad 2.
Tubercle
bacilli 3.
Tubercle
bacilli 4.
Tubercle
bacilli 5.
Broad 6.
Broad |
1.
Other
rifamycins 2.
None 3.
None 4.
None 5.
Other
rifamycins 6.
Other
rifamycins |
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Second-line agents |
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|
Kanamycin, amikacin,
streptomycin |
Aminoglycoside
antibiotics |
Broad |
Other aminoglycosides,
viomycin, capreomycin |
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|
Capreomycin, viomycin |
Tuberactinomycin
antibiotics |
Tubercle bacilli |
Aminoglycosides |
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Levofloxacin,
ofloxacin, moxifloxacin |
Quinolone antibiotics |
Broad |
None |
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Ethionamide,
prothionamide |
Thioamides |
Tubercle bacilli |
Thiacetazone |
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Cycloserine,
terizidone |
Synthetic |
Broad |
None |
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para-Aminosalicylic acid |
Synthetic |
Tubercle bacilli |
None |
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Third-line agents |
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|
Clofazimine |
Riminophenazine antileprotic |
Mycobacteria |
None |
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Amoxicillin/clavulonate |
β-lactam
antibiotic/β-lactamase inhibitor |
Broad |
None |
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Linezolid |
Oxazolindinone
antibiotic |
Broad |
None |
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|
Imipenem |
β-lactam antibiotic |
Broad |
None |
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Thiacetazone |
Synthetic |
Tubercle bacilli |
Ethionamide,
prothionamide |
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|
Clarithromycin |
Macrolide antibiotic |
Broad |
None |
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Bedaquiline |
Diarylquinoline
antibiotic |
Broad |
None |
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Delamanid |
Dihydro-nitro-imidazooxazole |
Mycobacteria |
None |
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Agents
that are active against M.
tuberculosis may also show activity against some other species of
mycobacteria. Strains of M.
bovis are naturally resistant to pyrazinamide. There are only
limited data on other activities of capreomycin and viomycin.
Current treatment regimens
The antituberculosis drugs currently
used in first line treatments are around 50 years old. The regimen that is
recommended by WHO and NICE for new cases of drug‐susceptible tuberculosis is highly efficacious, with cure
rates of around 90% in HIV‐negative
patients. The standard recommended regimen is 6 months of treatment with four
first line drugs: a combination of rifampicin, isoniazid, ethambutol and
pyrazinamide for 2 months, followed by a 4‐month continuation phase of rifampicin and isoniazid (the 6‐month four‐drug regimen).
Drug dosing schedule and common side effects
The
standard recommended regimen consists of four drugs:
1.
Isoniazid 5mg/kg/day (300 mg daily)
for the full 6 months.
2.
Rifampicin 10mg/kg/day (450 mg daily
for those weighing less than 50 kg; 600 mg daily for those above this weight)
for the full 6 months.
3.
Pyrazinamide for the first 2 months 25mg/kg/day
(1.5 g daily for those weighing less than 50 kg; 2.0 g daily for those above
this weight).
4.
Ethambutol for the first 2 months
(15 mg/kg body weight daily).
All the drugs are taken on an empty stomach once daily.
Isoniazid remains the standard drug, given in all regimens because of
its efficacy, cheapness and low toxicity. Its commonest side effects are peripheral
neuropathy (most common in elderly people), which can be countered by giving
pyridoxine (10 mg daily) prophylactically from the start of treatment, and
hepatitis in adults over 35 years of age.
Rifampacin can commonly cause elevated serum transaminases, during the
first 2 months of treatment, but therapy can usually be continued except in
severe cases. Urine, sweat and tears may be colored orange. The induction of
liver enzymes by rifampicin may reduce the effectiveness of oral
contraceptives.
Pyrazinamide causes hepatitis in 1%, and arthritis and the precipitation
of gout and cutaneous hypersensitivity in 3.5%.
Ethambutol may cause visual disturbances and rarely retrobulbar
neuritis, which is reversible if detected early. Patients should be warned of
this risk and advised to stop the drug if visual symptoms develop. Visual
acuity using a Snellen chart should be carried out before treatment starts. The
drug is best avoided in young children and in those with renal impairment.
In summary, all antituberculous
drugs may cause adverse reactions. In one study, reactions occurred in 10% of
patients treated.
|
MULTIDRUG-RESISTANT
AND EXTENSIVELY DRUG-RESISTANT TUBERCULOSIS |
|
Multidrug-resistant tuberculosis (MDR-TB) |
|
·
Resistant
to isoniazid and rifampin, the two most effective first-line drugs ·
Estimated
to account for ~3% of all new TB cases worldwide in 2015, but 20% of
individuals previously treated for TB |
|
Extensively drug-resistant tuberculosis (XDR-TB) |
|
·
Resistant
to isoniazid and rifampin ·
Resistant
to quinolones, the most effective second-line drugs ·
Resistant
to at least one of three injectable second-line drugs: amikacin, kanamycin,
or capreomycin ·
Estimated
to account for 10% of cases of MDR-TB |
The
CDC and WHO have outlined that XDR TB poses a grave global public health threat
and has a higher risk of death as it renders patients virtually untreatable
with currently available drugs.
Modification
for dermatological practice
The standard 6‐month regimen is effective in treating
cutaneous tuberculosis with a good clinical response and no relapses following
treatment.
The excision of small lesions of
lupus vulgaris or warty tuberculosis, if diagnosed early, may be effective.
Surgery may be helpful in scrofuloderma, sometimes shortening the time needed
for chemotherapy. Plastic surgery may help the disfigurement left by treated
lupus vulgaris.
Prognosis
Now revolutionized by modern
therapy, the prognosis depends largely on early and accurate diagnosis. When
tuberculosis has become generalized or has affected the meninges, the prognosis
must be doubtful. The mortality in patients with dual tuberculosis/HIV
infection is higher than in HIV‐negative
patients and the same applies in all forms of drug‐resistant tuberculosis. In infants
and young children, tuberculosis is always a serious disease.
Tuberculosis confined to the skin
usually responds well totherapy and a clinical response will usually occur
within 4–6 weeks, with lupus vulgaris showing a faster response time than
scrofuloderma.
BCG vaccination
BCG is a live attenuated strain of Mycobacterium
bovis used to immunize infants. While
current BCG vaccines protect against severe forms of tuberculosis in infants and young children (tuberculosis meningitis and miliary tuberculosis),
but its
ability to prevent pulmonary tuberculosis in adults remains
uncertain. Several studies have shown that
BCG does not appear to prevent skin tuberculosis. The protective effect of BCG
in children is likely to last at least 15 years.
Complications of BCG vaccination
In the normal course of BCG vaccination, a local reaction usually occurs
2–6 weeks later as a small papule that may slowly enlarge and discharge
purulent material to leave a shallow ulcer and then slowly heals,
leaving a scar. Vaccination may provoke an accelerated reaction in a previously
infected person. The regional lymph nodes may enlarge, but usually heal without
breaking down. Tuberculin sensitivity appears 5–6 weeks after vaccination.
Non‐specific reactions to BCG include urticaria and erythema
multiforme. Unusual reactions have also occurred, such as generalized
maculopapular or purpuric eruptions associated with arthralgia and abdominal
pain or myalgia, usually after repeated vaccination. Extensive or protracted
ulceration sometimes occurs.
Specific complications include
tuberculous processes caused by the BCG organism. Lupus vulgaris may develop at
the vaccination site, usually a few months, sometimes 3 years after vaccination.
Scrofuloderma has also been reported. Several of the tuberculids including
lichen scrofulosorum, an atypical popular tuberculid thought to be a variant of
papulonecrotic tuberculid and erythema induratum of Bazin have followed
vaccination. As these are hypersensitivity reactions to M. bovis,
antituberculous therapy is not necessary other than in immunocompromised
patients. Development of basal cell carcinoma in a BCG scar has been reported;
squamous cell carcinoma also developed in BCG‐induced lupus vulgaris in a 7‐year‐old
child.
