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Cutaneous adverse drug reactions to anti-tuberculosis drugs: state of the art and into the futureExpert Rev. Anti Infect. Ther. 10(4), 475–486 (2012)

Rannakoe J Lehloenya 1,2 and Keertan Dheda *2,3,4

1Division of Dermatology, Department of Medicine, University of Cape Town, Western Cape, South Africa 2Lung Infection and Immunity Unit, Division of Pulmonology, Department of Medicine & UCT Lung Institute, University of Cape Town, Western Cape, South Africa3Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Western Cape, South Africa 4Department 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

Anti-tuberculosis drugs are associated with sig-nifi cant 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 15– 20% of all ADRs. These include immunologically mediated drug hyper-sensitivity or nonimmune-mediated idiosyn-cratic reactions [1]. Common ADRs associated with anti-tuberculosis drugs include hepatitis, cutaneous adverse drug reactions ( CADR), nausea/ vomiting, inf luenza-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 confi ned to only the skin or be part of a multisystem disorder and may complicate anti-tuberculosis therapy with fi rst- and many second-line agents with a wide variety of clinical presentations. These include mor-biliform eruptions, Stevens–Johnson syndrome ( SJS), drug hypersensitivity syndrome ( DHS), cutaneous vasculitis, lichenoid drug eruption

and acute generalized exanthematous pustulosis. An individual drug can cause multiple types of CADR, and a specifi c type of CADR can be due to any drug [3–16]. CADR typically occurs dur-ing the fi rst few weeks of therapy [17]. In many patients, it presents as a self-limiting complica-tion with minor consequences; however, there may be considerable morbidity, mortality and signifi cant treatment interruption or a change in regimen. A good example is thioacetazone, which was identifi ed 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 HIV-infected 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

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 specifi c 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 identifi ed and a research agenda has been proposed.

KEYWORDS: adverse reactions • management • skin • therapy • tuberculosis

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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 [17,20,22–24]. 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 diffi -cult to identify offending drugs. Cotrimoxazole and nevirapine, used for P. jirovecii prophylaxis and HAART, respectively, are well established causes of severe CADR [25–27]. All these make TB-associated CADR a burgeoning problem for clinicians in high HIV-prevalence settings.

Epidemiology of anti-tuberculosis drug-associated CADRThe incidence of TB-associated CADR is unknown because of the inconsistency in the design of published studies, population differences, variable presentation, inaccurate reporting and limi-tations in case defi nitions and disease severity grading [28]. The lack of good studies makes it diffi cult to determine the impact of CADR on patient-related outcomes. Many epidemiological stud-ies 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 [6,30–33]. The limited available data suggest that the incidence of cutaneous hypersensi-tivity rashes due to anti-tuberculosis drugs is signifi cant. It ranged approximately 5.7% in a Malaysian hospital, 9% in Zambian children, 20% of HIV-seropositive patients receiving thioceta-zone 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 mortal-ity remains poorly defi ned, but it is clearly signifi cant and impacts on management [23].

Defi ning the severity of CADRIn 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 associ-ated with that specifi c type of CADR. SJS, TEN, DHS, cuta-neous vasculitis and bullous fi xed drug eruption are considered severe forms of CADR. Some authors defi ne 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 classifi cation of side effects used in assessing drugs for cancer therapy, is used extensively in clinical drug trials [37].

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 har-monize severity grading in reporting of all types of TB-associated CADR (TABLE 1) [38] has been suggested. This will enable pool-ing 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 insignifi cant in morbiliform eruptions to 30% in TEN [39]. Thus, it is important to identify the type of CADR as it infl uences management, including interruption of therapy and referral to higher levels of care. The types of anti-tuberculosis therapy-associated CADR are briefl y described in the following sections (FIGURE 1 & TABLE 2).

Morbiliform & maculopapular drug eruptionsMorbiliform (measles-like) drug eruption or maculopapular exan-thems are the most common presentation of a CADR, accounting for 95% of all cases [40]. The initial presentation, 7–14 days after initial exposure to the offending drug, is erythematous macules and papules starting centrally and spreading peripherally. In severe cases, the lesions become confl uent leading to erythro-derma. 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 syndromeDHS, 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), lymphadeno-pathy, leukocyte abnormalities (leucocytosis, eosinophilia and/or atypical lymphocytosis) and hepatitis [38,42]. Nephritis, pancreatitis, pneumonitis and myocarditis may be less fre-quently found. The eruption is often urticaria-like and macu-lopapular, but vesicles, pustules, cheilitis, purpura, targetoid lesions and erythroderma have been reported. The severity of the rash does not necessarily refl ect the extent of systemic involvement. The presence of a fever and facial edema suggest systemic disease. Long-standing severe lesions are character-ized 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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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 ery-thema and blisters of the palms and soles are a hallmark of SJS and TEN. They can be associated with signifi cant mortality in association with anti -tuberculosis therapy, including rifampicin, pyrazinamide, isoniazid, ethambutol, streptomycin, cycloserine and fl uoroquinolones [3,17,23,47–52].

Fixed drug eruptionFixed drug eruption usually presents as a solitary or numerous itchy, round well circumscribed, erythematous macules that

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 offend-ing 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 fl uoroquinolones [54–57].

Lichenoid drug eruptionLichenoid drug eruptions initially present as itchy small pink mac-ules that gradually progress to become fi rm violaceous, fl at-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

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 fl ushing or rash; drug fever <38°C; 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 <3.0–2.0 × 109 /l <2.0–1.0 × 109 /l <1.0 × 109 /l –

Neutrophil count decreased

< LLN to 1.5 × 109 /l <1.5–1.0 × 109 /l <1.0–0.5 × 109 /l <0.5 × 109 /l –

Platelets < LLN to 75 × 109 /l <75–50 × 109 /l <50–25 × 109 /l <25 × 109 /l –

Fever 38.0–39.0°C >39.0–40.0°C >40°C for 24 h >40°C for >24 h Death

Pruritus Mild or localized; topical intervention indicated

Intense or widespread; intermittent; skin changes from scratching; oral 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 10–30% 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 edema; limiting facial ADL

Severe swelling; 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 × U LN >asymptomatic with ALT; >3.0–5.0 × U LN

>5.0–20.0 × U LN; >5 × UL N for >2 weeks

>20 × U LN Death

AST increased > ULN to 3 × U LN >asymptomatic with ALT; >3.0–5.0 × U LN

>5.0–20.0 × U LN; >5 × UL N for >2 weeks

>20 × U LN Death

Creatinine > ULN to 1.5 × baseline

>1.5–3.0 × U LN; >1.5–3.0 × baseline

>3.0 × baseline; 3.0–6.0 × UL N

>6.0 × U LN 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].

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pattern called Wickham’s 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 spon-taneously, sometimes with persistent postinfl ammatory hyperpig-mentation. 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 fi ssuring of the skin [Lehloenya RJ. Lichenoid drug reaction

to anti-tuberculosis drugs treated through with topical steroids and

phototherapy (2012), Submitted]. Lichenoid drug eruption has been reported with isoniazid, pyrazinamide and ethambutol [8,34,58,59].

Cutaneous vasculitisThe diagnosis of drug-induced cutaneous vasculitis can be sus-pected clinically and its hallmark is palpable purpura, most

frequently on the lower limbs. Depending on severity of the reac-tion, the purpura can progress to become hemorrhagic blisters and ulcerate. As with all immune-complex mediated vasculitides, internal organ involvement, particularly involvement of the kid-ney, has to be excluded. Antituberculous therapy- associated vasculitis is rare, but has been reported with rifampicin and pyrazinamide [60–62].

There are other forms of CADR that are very rarely associ-ated with anti- tuberculosis therapy, including urticaria and photodermatitis [8,63,64].

Pathogenesis of TB-associated CADRThe pathogenesis of hypersensitivity reactions to all drugs, includ-ing 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

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 fi xed 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.

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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 pep-tides 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 suffi cient affi nity to activate T cells. The threshold of T-cell activation might be lowered by concomi-tant 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 specifi c HLA subtypes for example , in Han–Chinese, SJS/ TEN secondary to carbamezapine has an association with HLA-B*1502 in almost all cases [66]. Cytochrome P450 drug-metabolizing enzyme polymor-phisms ( CYP2C19 and CYP2C9) have recently been signifi cantly 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 patho-genesis, 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 pathomecha-nisms. However, the skin reacts in a limited number of ways to different types of drug-associated insults none of which are known to be specifi c for anti -tuberculosis drugs. The histology, immunohistochemical staining, and molecular and cellular bio logy of TB-associated CADR are yet to be defi ned. Further studies are needed to determine whether there are any unique characteristics specifi c to TB-associated CADR.

Diagnosis: identifying the offending drug when CADR occursA drug provocation test ( DPT), defi ned as a controlled admin-istration of a drug in order to diagnose drug hypersensitivity

reactions, is considered the gold standard in establishing causality [67]. 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-specifi c proliferation of T cells after in vitro stimulation with the suspected drug. However, this test has low specifi city of approximately 85% and sensitivity ranging from 30 to 70%, and after 30 years of use is still considered experimen-tal 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-specifi c cytokine release in vitro when lymphocytes from drug-sensitized patients are cocultured with the offending drug remains unex-plored. Possible candidate biomarkers that require exploration

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 7–14 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

Stevens–Johnson 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 fl at-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.

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 fi ve drug elimination cycles after the CADR

• Comedication that could affect the drug pharmacokinetic profi le 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 α-defensins, alarmins, activation marker C D69, I L-2, I L-5, I L-13 and I FN-γ [69–72]. Other possible markers are per-forin and granzyme B released by drug-specifi c cytotoxic T cells from the peripheral blood of affected patients. These molecules participate in drug-specifi c cytotoxic killing and can be assessed by Enzyme-linked immunosorbent spot o r fl ow cytometry [68]. Defi nitive studies are now needed to explore these possibilities.

Impact of treatment interruption on outcomesIn the case of drug-induced hepatitis both the American Thoracic Society and British Thoracic Society guidelines suggest stopping therapy in cases of signifi cant liver injury (defi ned by symptoms and the threefold rise in liver enzymes above a certain threshold) until res-olution of the hepatitis. Similarly, in the case of severe TB-associ ated CADR rein troduction 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 advan-tages of reducing morbidity and mortality due to drug withdrawal must be balanced against the risk of mortality due to treatment inter-ruption, 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 fi rst 2 w eeks. However, there are limited data on the interruption of TB treatm ent 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 analy-sis of 820 patients receiving fi rst-line anti-tuberculosis drugs, Tan et al. found a signifi cant association between treatment interruption and risk of death during the intensive phase of treatment (hazard ra tio: 3.20; p = 0.001) [34]. In a retrospective study of all factors associated with mortality in patients with drug-susceptible tubercu-lo sis reported to the San Francisco Tuberculo sis Control Program, treatment interruption, regardless of the reason, was shown to be signifi cantly associated with mortality during the intensive stages of therapy (hazard ratio: 3.15; 95% CI: 1. 52–6 .52; p = 0.002). In HIV-infec ted patients, this was associated with an even higher mortality (hazard ratio: 3.47; 95% CI: 1. 27–9 .50; p = 0.02). However, mortal-ity was signifi cantly associated with nonadherence with therapy but not with ADRs. The authors postulated that in contrast to ADRs, non adherence was associated with complete cessation of therapy [77]. This is further supported by evidence that adverse reactions do not have a signifi cant 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 expert s, which might be lacking in non-MDR treat ment protocols [78–80]. In a retrospective review of English patients, in both HIV-infec ted and HIV-uninf ected indi-viduals, the median delay in restarting treatment after all types of ADRs was 4 weeks b efore full anti-tuberculosis treatment could be restarted. This meant that most individuals required full TB retreat-ment. Almost all interruptions of anti-tuberculosis therapy occurred within the fi rst 2 months [29]. Thus, although there are no studies directly assessing the impact of treatment interruption following

TB-associated CADR, tre atment 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 signifi cant. 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 secon d- line anti-tuberculosis drugs they have not previ-ously been exposed to, while awaiting rechallenge, to minimize the impact of treatment interruption. These usually comprise drugs such as streptomycin, ethionamide, terizidone or a fl uoroquinolone. 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 second-line drugs used for the treatment of MDR and extensively drug-resistant (XDR) TB. It remains unclear how CADR impacts treat-ment outcomes in this group of patients. MDR and XDR TB are associated with poorer outcomes [81–83]. 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 haz-ard ratio: 1.17; 95% CI: 1.01–1.35) [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 down-stream patient adherence to therapy. Patients may be reluctant to take further treatment, which they perceive as toxic or unsafe. There are confl icting data about whether ADR in general impact on adherence to antituberculous drugs [29,85–87]. A better under-standing of this relationship is important for developing protocols and policy guidelines for optimal patient management.

Reintroduction of anti-tuberculosis therapy following TB-associated CADRThere are a limited number of effective anti-tuberculosis drugs and second-line drugs, which are less effective, have their own signifi cant toxicities and using them may prolong therapy by up to 24 months [88,89]. There is good evidence showing that rifampicin-based regimens are superior to nonrifampicin-based regimens with regard to unfavorable outcomes and relapse of TB [74,90,91].

Considering the signifi cant mortality associated with sub-optimally treated TB, it is justifi able to rechallenge patients who have experienced CADR-associated with fi rst-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 defi ned 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 specifi ed, making it diffi cult to assess utility of desensitiza-tion in various types of TB-associated CADR [95,96]. However,

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both approaches increase the risk of inducing additional and pos-sibly 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 signifi cant comorbidity, and those at increased risk due to severe or life-threatening reactions such as the bullous reac-tions, erythroderma, drug hypersensitivity syndrome, anaphy-laxis, 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 benefi t them.

How rechallenge should occur is another contentious issue. Whether rechallenge should occur at full dose or with incremen-tally increasing doses remain unclear. Sharma et al., in a well-designed 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 fi rst, whereas others sug-gest that the most effective drugs, namely rifampicin and isoniazid, should be reintroduced fi rst 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 mor-bidity associated with recurrence of CADR (on rechallenge) com-pared 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 HIV-infected compared to non- HIV; infected patients (hazard ratio: 2.4–2.9, 95% CI: 0.3–19.5, for isoniazid; hazard ratio: 8.0, 95% CI: 1.4 –43, for rifampicin; and hazard ratio: 2.1, 95% CI: 0.3–17.1, for pyrazinamide) [6]. Our own study in Cape Town, in a predomi-nantly HIV-infected population, found rifampicin to cause reintro-duction reactions in 57% of 23 patients who had DPT to fi rst-line TB drugs, supporting the fi ndings 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 retrospec-tive 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, respec-tively [38]. These fi ndings 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

not seem to affect the likelihood of developing a subsequent rein-troduction 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 [43,69,99–101]. In a retro-spective study in Zimbabwe, 13% of patients reacted when rechal-lenged 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-tuberculo-sis drugs each. The reason for multiple drug-related reactions is unclear. However, possibilities include: viral infections such as HIV, Epstein–Barr virus, cytomegalovirus and human herpes virus 6, where there is a signifi cant immune stimulation facili-tating an enhanced response to multiple drugs in susceptible individuals; crossreactivity of antigenic epitopes with structur-ally similar drugs (unlikely except with fl uoroquinolones and aminoglycosides) [43] and a true multiple drug hypersensitivity syndrome. Multiple drug hypersensitivity syndrome is defi ned as a well documented, repeated and clearly immune-mediated reaction to structurally unrelated drugs, possibly due to a defi cient tolerance mechanism against small chemical compounds.

HAART initiation in HIV- TB coinfected patients & CADRIn a recently published retrospective study of patients, with anti-tuberculosis 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 consider-ably. The issue of which drugs to implicate if CADR develops in coinfected patients and the timing and sequence of HAART rein-troduction is complex. When CADR develops in HIV- TB coin-fected 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 profi les of HAART, anti-tuberculosis therapy and drugs used for the prophylaxis or treatment of other opportunistic infections that are often initi-ated during this period [102]. It is recommended that antiretroviral therapy be initiated soon (within 2–8 weeks) after starting anti-tuberculosis therapy because early initiation of HAART low-ers the incidence of TB-associated deaths [103,104,201]. It is also known that anti-tuberculosis therapy-associated CADR occurs most frequently in the fi rst 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].

ConclusionThe incidence of TB-associated CADR may vary because of dis-ease burden, prescribing practices, ethnic differences, comorbidities

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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 high- and low-burden countries with TB (and HIV coinfection) to better inform on the optimal management of TB-associated CADR.

Expert commentary & fi ve-year viewTrials 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 impor-tant 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 devel-opments are likely to come from the use of in vitro tests to estab-lish causality in CADR, particularly those that measure cytokine secretion, upregulation of activation markers or gene expres-sion. This will help avoid the time consuming and potentially risky process of drug provocation testing. The increasing use of

pharmacogenomics holds a possibility of simple predictive genetic tests to rapidly and reliably screen for people who are susceptible to develop CADR to specifi c 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.

Financial & competing interests disclosureRJ 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 affi liations or fi nancial involvement with any organization or entity with a fi nancial interest in or fi nancial confl ict 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.

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

1. Understanding why HIV-infected people are more predisposed to developing TB-associated CADR2. Development of standardized case defi nitions and study designs to investigate TB-associated CADR3. 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 CADR4. Developing indications for interrupting therapy following TB-associated CADR5. Quantifying morbidity and mortality associated with TB-associated CADR compared to that associated with delay, interruption and

reintroduction of TB therapy6. 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 reintroduction7. Determining whether a delay in introducing HAART while reintroducing anti-tuberculosis drugs following TB-associated CADR

negatively impact on outcomes8. Determining the HLA associations with TB-associated CADR9. Determining the sensitivity and specifi city of in vitro tests to establish causality, particularly with nonproliferation assays. For example,

cytokine secretion, upregulation of activation markersCADR: Cutaneous adverse drug reactions; HAART: Highly active antiretroviral therapy; TB: Tuberculosis.

Key issues

• Cutaneous adverse drug reactions (CADR) may complicate anti-tuberculosis therapy with all fi rst- 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 defi nitions, 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 amplifi cation of drug resistance. The signifi cance 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 identifi cation of the offending drugs following TB-associated CADR.

• The limited effi cacy and high toxicities of second-line anti-tuberculosis drugs often make it necessary to reintroduce fi rst-line agents following tuberculosis-associated CADR. This carries a risk of recurrence of CADR, which must be balanced against the risk of suboptimal anti-tuberculosis therapy. The optimum balance between these two risks is patient specifi c 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.

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