Review

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Cutaneous adverse drug

reactions to anti-tuberculosis
drugs: state of the art and
into the future
Expert Rev. Anti Infect. Ther. 10(4), 475486 (2012)

Rannakoe J
Lehloenya1,2 and
Keertan Dheda*2,3,4
1
Division of Dermatology, Department
of Medicine, University of Cape Town,
Western Cape, South Africa
2
Lung Infection and Immunity Unit,
Division of Pulmonology, Department
of Medicine & UCT Lung Institute,
University of Cape Town,
Western Cape, South Africa
3
Institute of Infectious Diseases and
Molecular Medicine, University of
Cape Town, Western Cape,
South Africa
4
Department of Infection,
UCL Medical School, London, UK
*Author for correspondence:
Tel.: +27 21 406 7650
Fax: +27 21 406 7651
keertan.dheda@uct.ac.za

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First- and second-line anti-tuberculosis drugs are associated with a diverse presentation of
cutaneous adverse drug reactions (CADR), ranging from mild to life threatening. An individual
drug can cause multiple types of CADR, and a specific type of CADR can be due to any
anti-tuberculosis drug, which can make the management of tuberculosis (TB) following CADR
challenging. The higher incidence of TB and CADR in HIV-infected persons makes TB-associated
CADR a burgeoning problem for clinicians, particularly in high HIV-prevalence settings.
This review discusses the pathogenesis, epidemiology, clinical presentation, diagnosis and
management of TB-associated CADR. Clinical controversies including its impact on treatment
outcomes, challenges in restarting optimal anti-tuberculosis therapy and the timing of highly
active antiretroviral therapy initiation in those with HIV coinfection are also discussed. Finally,
gaps in the current knowledge of TB-associated CADR have been identified and a research
agenda has been proposed.
KEYWORDS: adverse reactions management skin therapy tuberculosis

Anti-tuberculosis drugs are associated with significant adverse drug reactions (ADRs), which
can make the treatment of tuberculosis (TB) a
challenge. ADRs can broadly be divided into
two types. Type A reactions are predictable,
dose-dependent and are the most common. Type
B ADRs are unpredictable, dose-independent
and comprise 1520% of all ADRs. These
include immunologically mediated drug hypersensitivity or nonimmune-mediated idiosyncratic reactions [1] . Common ADRs associated
with anti-tuberculosis drugs include hepatitis,
cutaneous adverse drug reactions ( CADR),
nausea/vomiting, influenza-like illness and
arthralgia [2] . In this review, CADR due to
anti-tuberculosis drugs, which are usually type
B reactions, will be focused on.
CADR can either be confined to only the skin
or be part of a multisystem disorder and may
complicate anti-tuberculosis therapy with firstand many second-line agents with a wide variety
of clinical presentations. These include morbiliform eruptions, StevensJohnson syndrome
(SJS), drug hypersensitivity syndrome (DHS),
cutaneous vasculitis, lichenoid drug eruption
10.1586/ERI.12.13

and acute generalized exanthematous pustulosis.

An individual drug can cause multiple types of
CADR, and a specific type of CADR can be due
to any drug [316] . CADR typically occurs during the first few weeks of therapy [17] . In many
patients, it presents as a self-limiting complication with minor consequences; however, there
may be considerable morbidity, mortality and
significant treatment interruption or a change
in regimen. A good example is thioacetazone,
which was identified early on as a common cause
of SJS/toxic epidermal necrolysis (TEN) in TB
and HIV coinfected patients. As a result of this,
WHO recommended avoiding the drug in HIVinfected patients with a subsequent decline of its
use worldwide [18] . Where treatment has been
empiric, the occurrence of CADR may often
result in a clinical conundrum because the
validity of the diagnosis is questioned.
The emergence of the HIV pandemic has had
a major impact on the incidence of TB. The
global incidence and mortality due to TB tripled
between 1990 and 2006 [19] . It is well established
that drug hypersensitivity reactions are more
common in HIV-infected persons. Although

2012 Expert Reviews Ltd

ISSN 1478-7210

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Lehloenya & Dheda

the reported incidence is widely variable, ranging from two to

100-fold, the lower value is likely a more realistic estimate [20,21] .
In addition, there is also a higher incidence of ADRs and CADR
to anti-tuberculosis drugs in HIV-infected persons [17,20,2224] .
Initiation of highly active antiretroviral therapy (HAART) and
Pneumocystis jirovecii pneumonia prophylaxis, often around the
same time as anti-tuberculosis therapy, can make it more difficult to identify offending drugs. Cotrimoxazole and nevirapine,
used for P. jirovecii prophylaxis and HAART, respectively, are
well established causes of severe CADR [2527] . All these make
TB-associated CADR a burgeoning problem for clinicians in
high HIV-prevalence settings.
Epidemiology of anti-tuberculosis drug-associated
CADR

The incidence of TB-associated CADR is unknown because of

the inconsistency in the design of published studies, population
differences, variable presentation, inaccurate reporting and limitations in case definitions and disease severity grading [28] . The
lack of good studies makes it difficult to determine the impact of
CADR on patient-related outcomes. Many epidemiological studies that evaluate the incidence and prevalence of TB-associated
ADRs do not classify CADR in any detail, often referring to them
as a rash or exanthem [4,6,29] . Some studies evaluating ADRs to
anti-tuberculosis therapy do not mention CADR, whereas it is
reported as the most common ADR in others [6,3033] . The limited
available data suggest that the incidence of cutaneous hypersensitivity rashes due to anti-tuberculosis drugs is significant. It ranged
approximately 5.7% in a Malaysian hospital, 9% in Zambian
children, 20% of HIV-seropositive patients receiving thiocetazone in Nairobi, Kenya, and 23% in a prospective Cameroonian
study of 235 patients receiving thiacetazone-free anti-tuberculosis
therapy [13,17,24,34] . In patients treated in an English hospital, 13%
of HIV-infected individuals had TB-associated CADR compared
with 8% of HIV-uninfected patients, severe enough to warrant
interruption of therapy [29] . The associated morbidity and mortality remains poorly defined, but it is clearly significant and impacts
on management [23] .
Dening the severity of CADR

In a prospective study of hospitalized French patients, prevalence

of CADR to all systemic drugs was 3.6/1000 patients with 34% of
cases being considered severe [35] . In a Chinese hospital 1.6/1000
hospital admissions were due to CADR of which 0.3/1000 were
considered severe [35,36] . However, no widely accepted grading
about the severity in CADR that is in general use. Severity is
often based on the type of drug reaction and mortality associated with that specific type of CADR. SJS, TEN, DHS, cutaneous vasculitis and bullous fi xed drug eruption are considered
severe forms of CADR. Some authors define severity based on
the need for hospitalization, interruption of therapy or change
of therapy. These are clearly not ideal defi nitions. Common
Terminology Criteria for Adverse Events grading, which is the
standardized classification of side effects used in assessing drugs
for cancer therapy, is used extensively in clinical drug trials [37] .
476

Recently, the CTACE guidelines when reporting the experience

with TB-associated CADR have been adapted, and adoption of
Common Terminology Criteria for Adverse Events grading to harmonize severity grading in reporting of all types of TB-associated
CADR (TABLE 1) [38] has been suggested. This will enable pooling of studies and improve understanding of these conditions in
different settings.
Types of CADR

CADR-associated mortality varies with the type of reactions

ranging from insignificant in morbiliform eruptions to 30% in
TEN [39] . Thus, it is important to identify the type of CADR as
it influences management, including interruption of therapy and
referral to higher levels of care. The types of anti-tuberculosis
therapy-associated CADR are briefly described in the following
sections (FIGURE 1 & TABLE 2) .
Morbiliform & maculopapular drug eruptions

Morbiliform (measles-like) drug eruption or maculopapular exanthems are the most common presentation of a CADR, accounting
for 95% of all cases [40] . The initial presentation, 714 days after
initial exposure to the offending drug, is erythematous macules
and papules starting centrally and spreading peripherally. In
severe cases, the lesions become confluent leading to erythroderma. In a great majority of cases, morbiliform drug eruptions
are self-limiting and treatment can continue uninterrupted [41] .
However, maculopapular exanthem can be the initial presentation
of more serious reactions such as SJS and DHS [23] . Worsening of
the rash, accompanied by systemic symptoms or mucositis, are
usually early indicators of severe disease and warrant stopping
treatment.
Drug hypersensitivity syndrome

DHS, which is also known as drug rash with eosinophilia and

systemic symptoms, drug-induced hypersensitivity syndrome or
hypersensitivity syndrome, is a severe disease that can be associated
with mortality of up to 10%. It is characterized by a long latency
period (>3 weeks), although on rechallenge it is usually within
72 h, fever, edema (particularly facial and acral), lymphadenopathy, leukocyte abnormalities (leucocytosis, eosinophilia
and/or atypical lymphocytosis) and hepatitis [38,42] . Nephritis,
pancreatitis, pneumonitis and myocarditis may be less frequently found. The eruption is often urticaria-like and maculopapular, but vesicles, pustules, cheilitis, purpura, targetoid
lesions and erythroderma have been reported. The severity
of the rash does not necessarily reflect the extent of systemic
involvement. The presence of a fever and facial edema suggest
systemic disease. Long-standing severe lesions are characterized by extensive scaling referred to as exfoliative dermatitis.
The clinical symptoms often persist for up to 2 weeks after
withdrawal of the offending drug [42] . DHS has been associated
with viral infections and reactivation particularly human herpes
virus 6 [43,44] . Anti-tuberculosis drugs that have been reported
to cause DHS include isoniazid, rifampicin, streptomycin and
pyrazinamide [34,45,46] .
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Cutaneous adverse drug reactions to anti-tuberculosis drugs

Review

Table 1. Adapted common terminology criteria for adverse events grading.

Adverse event

Grade 1: mild

Grade 2: moderate

Grade 3: severe

Grade 4: life
threatening

Grade 5:
death

Allergic reaction

Transient flushing
or rash;
drug fever <38C;
intervention not
indicated

Intervention indicated;
responds promptly to
symptomatic treatment;
prophylactic medication
indicated for 24 h

Prolonged; recurrence of
symptoms following initial
improvement; hospitalization
indicated for clinical sequelae

Life-threatening
consequences;
urgent intervention
indicated

Death

WCC low

< LLN to 3.0 109 /l <3.02.0 109 /l

<2.01.0 109 /l

<1.0 109 /l

Neutrophil count
decreased

< LLN to 1.5 109 /l <1.51.0 109 /l

<1.00.5 109 /l

<0.5 109 /l

Platelets

< LLN to 75 109 /l

<7550 109 /l

<5025 109 /l

<25 109 /l

Fever

38.039.0C

>39.040.0C

>40C for 24 h

>40C for >24 h

Death

Pruritus

Intense or widespread;
Mild or localized;
topical intervention intermittent; skin changes
from scratching; oral
indicated
intervention indicated;
limiting instrumental ADL

Intense or widespread;
constant; limiting self-care ADL
or sleep; oral corticosteroid or
immunosuppressive therapy
indicated

Rash
maculo-papular

Macules/papules
covering <10%
BSA with or
without symptoms

Macules/papules covering
1030% BSA with or
without symptoms;
limiting instrumental ADL

Macules/papules covering
>30% BSA with or without
symptoms; limiting self-care
ADL

Face edema

Localized facial
edema

Moderate localized facial

Severe swelling;
edema; limiting facial ADL limiting self-care ADL

Pain of skin

Mild pain

Moderate pain; limiting

instrumental ADL

Severe pain;
limiting self-care ADL

ALT increased

> ULN to 3 ULN

>asymptomatic with ALT;

>3.05.0 ULN

>5.020.0 ULN;
>5 ULN for >2 weeks

>20 ULN

Death

AST increased

> ULN to 3 ULN

>asymptomatic with ALT;

>3.05.0 ULN

>5.020.0 ULN;
>5 ULN for >2 weeks

>20 ULN

Death

Creatinine

> ULN to 1.5

baseline

>1.53.0 ULN;
>1.53.0 baseline

>3.0 baseline;
3.06.0 ULN

>6.0 ULN

Death

ADL: Activities of daily living; ALT: Alanine transaminase; AST: Aspartate aminotransferase; BSA: Body surface area; LLN: Lower limit of normal; ULN: Upper limit of
normal; WCC: White-cell count.
Reproduced with permission from [38].

SJS & TEN

SJS and TEN are considered as a spectrum of the same disease.

In SJS, there is <10% of epidermal detachment and in TEN there
is >30%. SJS/TEN overlap lies between these two extremes. The
early symptoms of fever, malaise, cough, stinging eyes and a sore
throat can be confused with an upper respiratory tract infection.
This rapidly progresses to an exanthem of macules and targetoid
lesions, epidermal detachment and mucositis. Early painful erythema and blisters of the palms and soles are a hallmark of SJS
and TEN. They can be associated with significant mortality in
association with anti-tuberculosis therapy, including rifampicin,
pyrazinamide, isoniazid, ethambutol, streptomycin, cycloserine
and fluoroquinolones [3,17,23,4752] .
Fixed drug eruption

Fixed drug eruption usually presents as a solitary or numerous

itchy, round well circumscribed, erythematous macules that
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evolve into edematous plaques on the skin or mucosae. The lesions

typically resolve with persistent hyperpigmentation. They tend
to recur in exactly the same sites on re-exposure to the offending drug, sometimes with new lesions erupting elsewhere. Apart
from the trunk, lips, palms, soles, glans penis and groin are
commonly affected. Occasionally, the lesions can be extensive
and bullous resembling SJS and toxic epidermal necrolysis [53] .
Fixed drug eruptions have been described with rifampicin and
fluoroquinolones [5457] .
Lichenoid drug eruption

Lichenoid drug eruptions initially present as itchy small pink macules that gradually progress to become firm violaceous, flat-topped,
polygonal and scaly papules. In some cases, the lesions persist as
macules, only increasing in size with continuing exposure to the
offending drug. The mucous membranes, particularly buccal and
genital mucosae, are favored sites with the characteristic white lace
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Lehloenya & Dheda

Figure 1. Anti-tuberculosis therapy-associated cutaneous adverse drug reactions. (A) Toxic epidermal necrolysis showing blisters
and epidermal stripping; (B) hyperpigmented round multiple lesions of fixed drug eruption; (C) purplish scaly plaques of lichenoid drug
eruption; (D) palpable purpura and blisters of drug-induced vasculitis; and (E) erythematous morbiliform lesions of drug hypersensitivity
syndrome.

pattern called Wickhams striae. The period between initiating

the drug and the development of the lesions ranges from days to
several years, with most cases occurring within a few months. On
withdrawal of the offending drug the lesions usually resolve spontaneously, sometimes with persistent postinflammatory hyperpigmentation. Continuation of therapy can result in worsening of
the eruption characterized by increasing pigmentation, sometimes
with focal areas of depigmentation, as well as thickening and
painful fissuring of the skin [Lehloenya RJ. Lichenoid drug reaction
to anti-tuberculosis drugs treated through with topical steroids and

frequently on the lower limbs. Depending on severity of the reaction, the purpura can progress to become hemorrhagic blisters
and ulcerate. As with all immune-complex mediated vasculitides,
internal organ involvement, particularly involvement of the kidney, has to be excluded. Antituberculous therapy-associated
vasculitis is rare, but has been reported with rifampicin and
pyrazinamide [6062] .
There are other forms of CADR that are very rarely associated with anti-tuberculosis therapy, including urticaria and
photodermatitis [8,63,64] .

phototherapy (2012), Submitted] . Lichenoid drug eruption has been

reported with isoniazid, pyrazinamide and ethambutol [8,34,58,59] .

Pathogenesis of TB-associated CADR

Cutaneous vasculitis

The diagnosis of drug-induced cutaneous vasculitis can be suspected clinically and its hallmark is palpable purpura, most
478

The pathogenesis of hypersensitivity reactions to all drugs, including anti-tuberculosis drugs, is not fully understood. However, these
reactions are known to involve many distinct immune mechanisms
and there are numerous hypotheses that have been proposed. The
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Cutaneous adverse drug reactions to anti-tuberculosis drugs

Review

Table 2. Summary and clinical features of different types of tuberculosis-associated cutaneous adverse
drug reactions.
Type of CADR

Clinical features

Morbiliform drug
eruption

Starts 714 days after the drug exposure as erythematous macules and papules. Rarely life threatening but
may signal a more severe reaction

Drug hypersensitivity
syndrome

Onset is approximately 3 weeks after drug exposure presenting as fever, edema, and a progressive
erythematous macules and papules often associated with eosinophilia and transaminitis

StevensJohnson
syndrome and toxic
epidermal necrolysis

At onset often confused with upper respiratory tract infection, which progresses to erythematous macules
and papules, targetoid lesions, epidermal detachment and mucositis. There is usually painful erythema and
blisters of the palms and soles

Fixed drug eruption

Initially appears as solitary or numerous round, well-circumscribed, erythematous itchy macules that resolve
with persistent hyperpigmentation recurring in exactly the same sites on re-exposure to the offending drug

Lichenoid drug eruption

Presents as itchy pink macules and purple flat-topped, polygonal and scaly papules. In mucous membranes,
there is the characteristic white lacy pattern

Cutaneous vasculitis

Usually found on the lower limbs where it presents as palpable purpura, hemorrhagic blisters and ulcers. Can
be associated with systemic disease, particularly involving the kidney

CADR: Cutaneous adverse drug reaction.

hapten theory suggests that small molecules like drugs called

haptens, which are not normally antigenic or immunogenic, can
become so by covalently binding to a larger protein or peptide.
Chemically inert drugs, which do not covalently bind to peptides or proteins, can directly bind to T-cell receptors or MHC
molecules via van der Waals forces, or electrostatic and hydrogen
bonds. These drugs bind with sufficient affinity to activate T cells.
The threshold of T-cell activation might be lowered by concomitant immune dysregulation and stimulation of T cells as seen in
HIV infection or herpes virus coinfection [65] . This activation of
cytotoxic T cells is thought to be the major mechanism of cell
injury. Reactions to some drugs are associated with specific HLA
subtypes for example, in HanChinese, SJS/TEN secondary to
carbamezapine has an association with HLA-B*1502 in almost all
cases [66] . Cytochrome P450 drug-metabolizing enzyme polymorphisms (CYP2C19 and CYP2C9) have recently been significantly
associated with the risk of developing TB-associated morbiliform
eruption in comparison to patients who tolerated anti-tuberculosis
therapy. More studies are needed to further characterize the pathogenesis, as well as the association, between the genetic predisposition
and TB-associated CADR.
The skin is accessible and relatively easy and safe to biopsy.
Samples taken from the reaction site can provide information
on the type of drug reaction and the underlying pathomechanisms. However, the skin reacts in a limited number of ways
to different types of drug-associated insults none of which are
known to be specific for anti-tuberculosis drugs. The histology,
immunohistochemical staining, and molecular and cellular
biology of TB-associated CADR are yet to be defined. Further
studies are needed to determine whether there are any unique
characteristics specific to TB-associated CADR.
Diagnosis: identifying the offending drug when
CADR occurs

A drug provocation test (DPT), defined as a controlled administration of a drug in order to diagnose drug hypersensitivity
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reactions, is considered the gold standard in establishing causality

The European Network for Drug Allergy and the European
Academy of Allergology and Clinical Immunology interest group
on hypersensitivity has developed guidelines for DPT (BOX 1) [28,67] .
In drug-sensitized patients, the lymphocyte transformation test
has been used to measure drug-specific proliferation of T cells after
in vitro stimulation with the suspected drug. However, this test has
low specificity of approximately 85% and sensitivity ranging from
30 to 70%, and after 30 years of use is still considered experimental and complementary to other tests. It has several disadvantages,
including requirement for sterile culture, labor-intensive relative
to its diagnostic accuracy, and requires working with radioactive
materials and expensive equipment [68] . The role of drug-specific
cytokine release in vitro when lymphocytes from drug-sensitized
patients are cocultured with the offending drug remains unexplored. Possible candidate biomarkers that require exploration
[67] .

Box 1. The European Network for Drug Allergy and

the European Academy of Allergology and Clinical
Immunology interest group guidelines for drug
provocation testing.
Administer the drugs via the same route and in the same form
that it was originally taken
Use escalating doses
Rechallenge should start at least 4 weeks or five drug
elimination cycles after the CADR
Comedication that could affect the drug pharmacokinetic
profile should be eliminated
The patient should be in good health with no comorbidity risks
There should be no alternate tests available to aid diagnosis
Rechallenge should take place in a controlled environment with
resuscitation facilities
Good documentation following controlled protocols and
assessment systems should be used to document responses
Data taken from [67].

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include -defensins, alarmins, activation marker CD69, IL-2,

IL-5, IL-13 and IFN- [6972] . Other possible markers are perforin and granzyme B released by drug-specific cytotoxic T cells
from the peripheral blood of affected patients. These molecules
participate in drug-specific cytotoxic killing and can be assessed
by Enzyme-linked immunosorbent spot or flow cytometry [68] .
Definitive studies are now needed to explore these possibilities.
Impact of treatment interruption on outcomes

In the case of drug-induced hepatitis both the American Thoracic

Society and British Thoracic Society guidelines suggest stopping
therapy in cases of significant liver injury (defined by symptoms and
the threefold rise in liver enzymes above a certain threshold) until resolution of the hepatitis. Similarly, in the case of severe TB-associated
CADR reintroduction of anti-tuberculosis therapy is instituted once
the clinical and laboratory parameters (depending on the organ
coinvolved) have returned to baseline [73,74] . There is some evidence
that withdrawal of the offending drug improves outcomes in severe
CADR; so therapy is usually interrupted [75,76] . However, the advantages of reducing morbidity and mortality due to drug withdrawal
must be balanced against the risk of mortality due to treatment interruption, enhancing the development of drug resistance due to mono
or dual drug therapy, and driving disease transmission by infectious
patients to other patients, staff and the community if treatment is
interrupted in the first 2 weeks. However, there are limited data on
the interruption of TB treatment as a direct consequence of CADR
with most of the current knowledge based on interruption for any
reason, including nonadherence or any ADR. In a multivariate analysis of 820 patients receiving first-line anti-tuberculosis drugs, Tan
et al. found a significant association between treatment interruption
and risk of death during the intensive phase of treatment (hazard
ratio: 3.20; p = 0.001) [34] . In a retrospective study of all factors
associated with mortality in patients with drug-susceptible tuberculosis reported to the San Francisco Tuberculosis Control Program,
treatment interruption, regardless of the reason, was shown to be
significantly associated with mortality during the intensive stages of
therapy (hazard ratio: 3.15; 95% CI: 1.526.52; p = 0.002). In HIVinfected patients, this was associated with an even higher mortality
(hazard ratio: 3.47; 95% CI: 1.279.50; p = 0.02). However, mortality was significantly associated with nonadherence with therapy but
not with ADRs. The authors postulated that in contrast to ADRs,
nonadherence was associated with complete cessation of therapy
[77] . This is further supported by evidence that adverse reactions do
not have a significant negative impact on treatment outcomes in
multidrug-resistant (MDR) TB, particularly in patients who were
adherent to therapy. However, this is achieved with proper protocols,
support and involvement of TB experts, which might be lacking in
non-MDR treatment protocols [7880] . In a retrospective review of
English patients, in both HIV-infected and HIV-uninfected individuals, the median delay in restarting treatment after all types of
ADRs was 4 weeks before full anti-tuberculosis treatment could be
restarted. This meant that most individuals required full TB retreatment. Almost all interruptions of anti-tuberculosis therapy occurred
within the first 2 months [29] . Thus, although there are no studies
directly assessing the impact of treatment interruption following
480

TB-associated CADR, treatment interruption in general may impact

on disease outcome (culture conversion and mortality). Treatment
interruption following CADRs is usually temporary, but depending
on the severity, the duration of interruption can be significant. It is
thus suggested that patients who are clinically ill and who warrant
the initiation of treatment, therapy should be started under cover of
two to three second-line anti-tuberculosis drugs they have not previously been exposed to, while awaiting rechallenge, to minimize the
impact of treatment interruption. These usually comprise drugs such
as streptomycin, ethionamide, terizidone or a fluoroquinolone. It is
clear that further studies are needed to determine the impact of drug
interruption on treatment outcomes following CADR.
There are limited data about CADR in the context of secondline drugs used for the treatment of MDR and extensively drugresistant (XDR) TB. It remains unclear how CADR impacts treatment outcomes in this group of patients. MDR and XDR TB
are associated with poorer outcomes [8183] . However, in cases of
MDR TB, each additional month in which a patient failed to take
at least 80% of their prescribed drugs was associated with nearly
an additional 20% hazard of developing XDR TB (adjusted hazard ratio: 1.17; 95% CI: 1.011.35) [84] . Further studies are now
needed to determine the incidence of CADR with second-line
drugs and the risk of impacting outcomes and enhancing drug
resistance in this context.
It is also unclear whether TB-associated CADR impacts downstream patient adherence to therapy. Patients may be reluctant to
take further treatment, which they perceive as toxic or unsafe.
There are conflicting data about whether ADR in general impact
on adherence to antituberculous drugs [29,8587] . A better understanding of this relationship is important for developing protocols
and policy guidelines for optimal patient management.
Reintroduction of anti-tuberculosis therapy following
TB-associated CADR

There are a limited number of effective anti-tuberculosis drugs

and second-line drugs, which are less effective, have their own
significant toxicities and using them may prolong therapy by up to
24 months [88,89] . There is good evidence showing that rifampicinbased regimens are superior to nonrifampicin-based regimens
with regard to unfavorable outcomes and relapse of TB [74,90,91] .
Considering the significant mortality associated with suboptimally treated TB, it is justifiable to rechallenge patients who
have experienced CADR-associated with first-line drugs. This is
to establish causality and eliminate the offending drug from the
treatment regimen [92] . However, this approach increases the risk of
inducing additional and possibly a fatal CADR. The other option is
desensitization that is defined as loss of response after prolonged or
repeated application of stimulus [93] . The term has been used more
loosely in relation to SJS/TEN following TB therapy to describe
escalating doses with the aim of eliminating the offending drug
from the treatment regimen. Oral desensitization has been used
successfully in TB-associated CADR with IgE-mediated reactions
and DHS [94] . However, in most studies the type of CADR is often
not specified, making it difficult to assess utility of desensitization in various types of TB-associated CADR [95,96] . However,
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Cutaneous adverse drug reactions to anti-tuberculosis drugs

both approaches increase the risk of inducing additional and possibly a fatal CADR. Thus, the risk of reintroduction reactions
must be balanced against the morbidity and mortality associated
with less effective regimens. There are limited data to guide the
reintroduction (rechallenge) of drugs in TB-associated CADR.
Traditional contraindications to rechallenge include pregnancy,
those with significant comorbidity, and those at increased risk due
to severe or life-threatening reactions such as the bullous reactions, erythroderma, drug hypersensitivity syndrome, anaphylaxis, systemic vasculitis and drug-induced autoimmune disease.
There are obvious limitations to these recommendations, based
on expert opinion, and further studies are required to establish
their validity (BOX 1) . Exclusion of these patients to rechallenge may
place them at unacceptably high risk of tuberculosis-associated
morbidity and mortality. It is also crucial, if possible, to perform
drug sensitivity testing before rechallenge is attempted. This
will avoid exposing the patient to a potentially life-threatening
reaction to a drug that will not benefit them.
How rechallenge should occur is another contentious issue.
Whether rechallenge should occur at full dose or with incrementally increasing doses remain unclear. Sharma et al., in a welldesigned study, showed that full dose rechallenge versus dose
escalation is not associated with more reintroduction reactions
in anti-tuberculosis drug-induced hepatitis [97] .
Furthermore, the sequence in which the drugs are reintroduced
is still contentious. Some authors suggest that the drugs least likely
to cause a reaction should be reintroduced first, whereas others suggest that the most effective drugs, namely rifampicin and isoniazid,
should be reintroduced first to minimize the risks of suboptimal
therapy [52,74,98] . In cases reported in the literature, the sequence of
reintroduction was arbitrarily selected [5] . The mortality and morbidity associated with recurrence of CADR (on rechallenge) compared to that associated with suboptimal anti-tuberculosis therapy
is unknown. To further complicate matters, there is disagreement
on which of the currently used drugs are most frequently implicated
as causing CADR. Some authors suggest that pyrazinamide is the
most frequent offender, whereas others suggest streptomycin [6,22] .
Yee et al. found rifampicin to be the most frequent offender in HIVinfected compared to non-HIV; infected patients (hazard ratio:
2.42.9, 95% CI: 0.319.5, for isoniazid; hazard ratio: 8.0, 95%
CI: 1.443, for rifampicin; and hazard ratio: 2.1, 95% CI: 0.317.1,
for pyrazinamide) [6] . Our own study in Cape Town, in a predominantly HIV-infected population, found rifampicin to cause reintroduction reactions in 57% of 23 patients who had DPT to first-line
TB drugs, supporting the findings of Yee et al. [6,38] .
When and how to rechallenge in the setting of TB-associated
CADR remains to be conclusively determined. In a retrospective study performed in Cape Town, 22 out of 23 reintroduction
reactions occurred within 72 h of reintroducing the offending
drug. Itch, hepatitis and fever were the most frequent reactions in
23 patients occurring in 48, 39 and 35% of the patients, respectively [38] . These findings were made in hospitalized patients with
strict monitoring and the drugs were withdrawn at the earliest sign
of a reintroduction reaction and before worsening of laboratory
and clinical parameters. The severity of the original hepatitis does
www.expert-reviews.com

Review

not seem to affect the likelihood of developing a subsequent reintroduction reaction. Larger prospective studies are now needed
to guide clinicians performing DPT in TB-associated CADR.
Until all these issues are resolved, clinical decision making will
be constrained by lack of evidence-based data.
Clinicians should be aware that reintroduction reactions to
multiple drugs during DPT have been reported for many classes
of drugs, including anti-tuberculosis drugs [43,69,99101] . In a retrospective study in Zimbabwe, 13% of patients reacted when rechallenged with multiple anti-tuberculosis drugs [22] . On the other
hand, in our own study, four out of 23 patients who developed
reintroduction reactions on DPT reacted to two anti-tuberculosis drugs each. The reason for multiple drug-related reactions is
unclear. However, possibilities include: viral infections such as
HIV, EpsteinBarr virus, cytomegalovirus and human herpes
virus 6, where there is a significant immune stimulation facilitating an enhanced response to multiple drugs in susceptible
individuals; crossreactivity of antigenic epitopes with structurally similar drugs (unlikely except with fluoroquinolones and
aminoglycosides) [43] and a true multiple drug hypersensitivity
syndrome. Multiple drug hypersensitivity syndrome is defined
as a well documented, repeated and clearly immune-mediated
reaction to structurally unrelated drugs, possibly due to a deficient
tolerance mechanism against small chemical compounds.
HAART initiation in HIV-TB coinfected patients & CADR

In a recently published retrospective study of patients, with antituberculosis therapy-associated CADR, seen between 2001 and
2009 in Cape Town, only one out of 60 HIV-infected patients
were on HAART when they developed the initial drug reaction
[38] . However in 2011, HAART coverage has increased considerably. The issue of which drugs to implicate if CADR develops in
coinfected patients and the timing and sequence of HAART reintroduction is complex. When CADR develops in HIV-TB coinfected patients on HAART, all drug therapy is usually stopped.
HAART is recommenced after the reintroduction of anti-TB
therapy. Determining the offending drug in this setting is further
complicated by the overlapping adverse effect profiles of HAART,
anti-tuberculosis therapy and drugs used for the prophylaxis or
treatment of other opportunistic infections that are often initiated during this period [102] . It is recommended that antiretroviral
therapy be initiated soon (within 28 weeks) after starting antituberculosis therapy because early initiation of HAART lowers the incidence of TB-associated deaths [103,104,201] . It is also
known that anti-tuberculosis therapy-associated CADR occurs
most frequently in the first 100 days after initiation of therapy [33] .
This period also coincides with restoration of host immunity and
development of TB-associated immune reconstitution syndrome
(IRIS) [105] . Thus, diagnostic uncertainty may arise (infection vs
IRIS vs ADR), particularly at low CD4 counts. In addition, it is
hypothesized that DHS itself may be a form of IRIS [106] .
Conclusion

The incidence of TB-associated CADR may vary because of disease burden, prescribing practices, ethnic differences, comorbidities
481

Review

Lehloenya & Dheda

Box 2. Tuberculosis-associated cutaneous adverse drug reactions research agenda.

1. Understanding why HIV-infected people are more predisposed to developing TB-associated CADR
2. Development of standardized case definitions and study designs to investigate TB-associated CADR
3. Determining the frequency with which the individual anti-tuberculosis drugs cause TB-associated CADR in different settings. For
example, in HIV-infected patients and different types of CADR
4. Developing indications for interrupting therapy following TB-associated CADR
5. Quantifying morbidity and mortality associated with TB-associated CADR compared to that associated with delay, interruption and
reintroduction of TB therapy
6. Determining which is the safest and most effective method of reintroducing anti-tuberculosis drugs? For example, sequential and
cumulative dose escalation versus full dose rechallenge, desensitization to the offending drug or sequence of reintroduction
7. Determining whether a delay in introducing HAART while reintroducing anti-tuberculosis drugs following TB-associated CADR
negatively impact on outcomes
8. Determining the HLA associations with TB-associated CADR
9. Determining the sensitivity and specificity of in vitro tests to establish causality, particularly with nonproliferation assays. For example,
cytokine secretion, upregulation of activation markers
CADR: Cutaneous adverse drug reactions; HAART: Highly active antiretroviral therapy; TB: Tuberculosis.

and nutritional status. However, in high HIV-prevalence settings,

TB-associated CADR is common and management is complex.
There are large gaps in the knowledge about several aspects of
TB-associated CADR (BOX 2) . Studies are now needed in both highand low-burden countries with TB (and HIV coinfection) to better
inform on the optimal management of TB-associated CADR.

pharmacogenomics holds a possibility of simple predictive genetic

tests to rapidly and reliably screen for people who are susceptible
to develop CADR to specific anti-tuberculosis drugs as has been
done for drugs such as allopurinol and carbamezapine in some
populations. Finally, new anti-tuberculosis drugs in development
will reduce the need for drug provocation testing by providing
more therapeutic options.

Expert commentary & ve-year view

Trials that are currently underway will lead to more robust data
on anti-tuberculosis-associated CADR and guide development
guidelines on management of these patients. HIV plays an important role in both TB and CADR, and studies have to be done in
both high and low HIV burden settings so that management can
be adapted appropriately. The most promising and exciting developments are likely to come from the use of in vitro tests to establish causality in CADR, particularly those that measure cytokine
secretion, upregulation of activation markers or gene expression. This will help avoid the time consuming and potentially
risky process of drug provocation testing. The increasing use of

Financial & competing interests disclosure

RJ Lehloenya is supported by the Discovery Foundation, Dermatological

Society of South Africa and is a recipient of Carnegie Corporation Infectious
Disease award. K Dheda is supported by the South African National Research
Foundation, the South African Medical Research Council, EU FP7 and the
European and Developing Countries Clinical Trials Partnership (EDCTP).
The authors have no other relevant affiliations or financial involvement
with any organization or entity with a financial interest in or financial
conflict with the subject matter or materials discussed in the manuscript
apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.

Key issues
Cutaneous adverse drug reactions (CADR) may complicate anti-tuberculosis therapy with all first- and several second-line
antituberculous agents with a wide variety of clinical presentations.
HIV infection is associated with an increased risk of tuberculosis-associated CADR.
The incidence of tuberculosis-associated CADR is unknown because of inconsistent reporting in the literature. Harmonization of case
definitions, severity grading, study design and an awareness of population differences are required.
Different types of CADR carry different risks of mortality and morbidity, and it is prudent for clinicians to recognize them and manage
them accordingly.
Interruption of anti-tuberculosis therapy is frequent in CADR and this may be associated with increased mortality, morbidity and
possibly the amplification of drug resistance. The significance of these associations is unclear and more studies are needed.
Initiation of highly active antiretroviral therapy, anti-tuberculosis therapy and prophylaxis for opportunistic infections concurrently
complicates the identification of the offending drugs following TB-associated CADR.
The limited efficacy and high toxicities of second-line anti-tuberculosis drugs often make it necessary to reintroduce first-line agents following
tuberculosis-associated CADR. This carries a risk of recurrence of CADR, which must be balanced against the risk of suboptimal antituberculosis therapy. The optimum balance between these two risks is patient specific and further studies are needed to clarify this issue.
The drug provocation test is considered the gold standard to identify the offending drug. It may be positive to multiple anti-tuberculosis drugs.
There are many unanswered questions including the sequence of reintroduction of anti-tuberculosis drugs, dosing schedules and the
merits of sequential full dose rechallenge versus sequential escalating dose rechallenge. Several appropriately designed studies will be
required to address these questions.

482

Expert Rev. Anti Infect. Ther. 10(4), (2012)

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