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The imagery of pigmented skin is underrepresented in teaching materials such as textbooks, journals, and online references, and this has resulted in poorer diagnostic and management outcomes of skin pathology, including delayed cutaneous drug hypersensitivity reactions. In this review, we use clinical images to highlight factors that impact clinical presentations and sequelae of drug hypersensitivity reactions in pigmented skin compared with nonpigmented skin. We describe clinical features in some anatomic sites that aid diagnosis or are associated with more severe sequelae. Finally, we discuss strategies that may aid the diagnosis and management of these reactions in pigmented skin.

PURPOSE OF REVIEW: Immune-mediated adverse drug reactions (IM-ADRs) are many times more common in HIV-infected patients. Usual offending drugs include antiretroviral and antiinfectives, but the burden of specific drug IM-ADRs is population-specific; changing as new and fixed dose combinations enter the market, and drug-resistance patterns demand. This review considers recent literature on epidemiology, mechanisms, clinical management and prevention of IM-ADRs amongst persons living with HIV/AIDS. RECENT FINDINGS: Epidemiological studies continue to describe high rates of delayed hypersensitivity to known offenders, as well as similar reactions in preexposure prophylaxis. IM-ADRs to oral and injectable integrase strand transfer inhibitors are reported with expanding use. The clinical spectrum and management of IM-ADRs occurring in HIV-infected populations is similar to uninfected; with exceptions such as a recently described severe delayed efavirenz DILI with high mortality. Furthermore, the context can be unique, such as the lower than expected mortality in a Stevens–Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) cohort from a HIV/TB high burden setting. Programmatic data showing the near complete elimination of Abacavir drug hypersensitivity syndrome following implementation of HLA-B57:01 screening is a stellar example of how prevention is possible with mechanistic insight. SUMMARY: IM-ADRs remain a challenge in persons living with HIV. The complexities posed by polypharmacy, overlapping drug toxicities, drug interactions, overlap of IM-ADRs with other diseases, limited alternative drugs, and vulnerable patients with advanced immunosuppression with high mortality, necessitate increased use of drug provocation testing, treat-through and desensitization strategies. There is an urgent need for improved diagnostics and predictive biomarkers for prevention, or to guide treat-through, rechallenge and desensitization approaches.

The authors regret not all contributing authors correctly acknowledged funding. Jonathan Peter’s IMARI-Africa project (AFRISCAR) is part of the EDCTP2 programme supported by the European Union (grant number TMA2017SF-1981 ). The authors would like to apologise for any inconvenience caused.

Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) is a life-threatening, immunologically-mediated and usually drug-induced disease with a high burden to individuals, their families and society with an annual incidence of 1–5/1,000,000. To effect significant reduction in short- and long-term morbidity and mortality, and advance clinical care and research, coordination of multiple medical, surgical, behavioral, and basic scientific disciplines is required. On March 2, 2017 an investigator-driven meeting was held immediately prior to the American Academy of Dermatology Annual meeting for the central purpose of assembling, for the first time in the United States, clinicians and scientists from multiple disciplines involved in SJS/TEN clinical care and basic science research. As a product of this meeting, this article summarizes the current state of knowledge and expert opinion related to SJS/TEN covering a broad spectrum of topics including epidemiology and pharmacogenomic networks; clinical management and complications; special populations such as pediatrics, the elderly, and pregnant women; regulatory issues and the electronic health record; new agents that cause SJS/TEN; pharmacogenomics and immunopathogenesis; and the patient perspective. Goals include the maintenance of a durable and productive multidisciplinary network that will significantly further scientific progress and translation into prevention, early diagnosis, and management of SJS/TEN. ©2017 American Academy of Allergy, Asthma & Immunology (J Allergy Clin Immunol Pract 2018;6:38–69)

The majority of immune-mediated adverse drug reactions (IM-ADRs) involve the skin, and many have additional systemic features. Severe cutaneous adverse drug reactions (SCAR) are an uncommon, potentially life-threatening and challenging sub-group of IM-ADRs with diverse clinical phenotypes, mechanisms and offending drugs. T-cell mediated immunopathology is central to these severe delayed reactions, but effector cells and cytokines differ by clinical phenotype. Strong HLA-gene associations have been elucidated for specific drug-SCAR IM-ADRs such as Stevens-Johnson Syndrome/toxic epidermal necrolysis (SJS/TEN); although the mechanisms by which carriage of a specific HLA allele is necessary but not sufficient for the development of many IM-ADRs is still being defined. SCAR management is complicated by substantial short and long-term morbidity/ mortality and the potential need to treat ongoing co-morbid disease with related medications. Multidisciplinary specialist teams at experienced units should care for patients. In the setting of SCAR, patient outcomes as well as preventive,diagnostic, treatment and management approaches are often not generalizable, but rather context specific, driven by population HLA-genetics, the pharmacology and genetic risk factors of the implicated drug, severity of underlying co-morbid disease necessitating ongoing treatments, and cost considerations. In this review, we update the basic and clinical science of SCAR diagnosis and management.

Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are potentially life-threatening, immune-mediated adverse reactions characterized by widespread erythema, epidermal necrosis, and detachment of skin and mucosa. Efforts to grow and develop functional international collaborations and a multidisciplinary interactive network focusing on SJS/TEN as an uncommon but high burden disease will be necessary to improve efforts in prevention, early diagnosis and improved acute and long-term management. SJS/TEN 2019: From Science to Translation was a 1.5-day scientific program held April 26-27, 2019, in Vancouver, Canada. The meeting successfully engaged clinicians, researchers, and patients and conducted many productive discussions on research and patient care needs.

To compare the cost of managing treatment-limiting cutaneous adverse drug reactions (CADRs) to first-line anti-tuberculosis drugs to an alternative strategy of immediate treatment initiation using second-line drugs in a South African setting.Clinical and cost data were retrospectively collected from patients presenting with a first-line anti-tuberculosis therapy-associated CADR. Costs (2016 US$) were estimated using an ingredient's approach from a healthcare provider perspective. The per-patient and total cost of drug rechallenge, the current management strategy for severe CADR, was calculated. Alternative strategies involving second-line treatment were derived from literature and expert clinical advice.Drug rechallenge costs US $5831 (95% CI: 5134-6527) per patient. Hospitalisation accounted for 62% of this cost. Alternative CADR management strategies using regimens containing rifabutin, bedaquiline and/or delamanid cost 44%-55% less than drug rechallenge (US $2651-US $3276/patient). In univariate sensitivity analyses, drug rechallenge and alternative strategies were most sensitive to hospitalisation and tuberculosis drug costs, respectively.Cutaneous adverse drug reactions to anti-tuberculosis treatment represent a significant economic burden. An alternate strategy of outpatient-initiated second-line therapy is economically feasible but requires clinical validation to assess effectiveness.Comparer le coût de la prise ne charge des effets indésirables cutanés (EIC) limitant le traitement aux antituberculeux de première ligne à celui d'une stratégie alternative d'initiation immédiate du traitement par des médicaments de deuxième ligne dans un contexte sud-africain. MÉTHODES: Les données cliniques et les coûts ont été collectés rétrospectivement chez des patients présentant un EIC associé au traitement antituberculeux de première ligne. Les coûts (USD, 2016) ont été estimés en utilisant une approche d'ingrédient du point de vue d'un prestataire de soins de santé. Le coût par patient et le coût total du nouveau traitement, de la stratégie actuelle de prise en charge des cas d’EIC sévère, ont été calculés. Des stratégies alternatives impliquant un traitement de deuxième ligne ont été dérivées de la littérature et de conseils cliniques d'experts. RÉSULTATS: Le coût du nouveau traitement était de 5.831 USD (IC95%: 5.134 - 6.527) par patient. L'hospitalisation représentait 62% de ce coût. Les stratégies alternatives de prise en charge des EIC utilisant des schémas thérapeutiques contenant de la rifabutine, de la bédaquiline et/ou du delamanide coûtent de 44 % à 55 % moins cher que le nouveau traitement (2.651 USD - 3.276 USD/patient). Dans les analyses de sensibilité univariées, les stratégies de re-traitement et les stratégies alternatives étaient plus sensibles aux coûts d'hospitalisation et de médicaments antituberculeux, respectivement.Les EIC des antituberculeux représentent une charge économique importante. Une stratégie alternative de traitement de deuxième ligne mise en place chez des patients ambulatoires est économiquement réalisable mais nécessite une validation clinique pour évaluer l'efficacité.

International audience; Controversies exist with regard to in vivo approaches to delayed immunologically mediated adverse drug reactions, such as exanthem (maculopapular eruption), drug reaction with eosinophilia and systemic symptoms, acute generalized exanthematous pustulosis, Stevens-Johnson syndrome/toxic epidermal necrolysis, and fixed drug eruptions. In particular, widespread differences exist between regions and practice on the availability and use of intradermal and patch testing, the standard drug concentrations used, the use of additional drugs in intradermal and patch testing to help determine cross-reactivity, the timing of testing in relation to the occurrence of the adverse drug reaction, the use of testing in specific phenotypes, and the use of oral challenge in conjunction with delayed intradermal and patch testing to ascertain drug tolerance. It was noted that there have been advances in the science of delayed T cell-mediated reactions that have shed light on immunopathogenesis and provided a mechanism of preprescription screening in the case of HLA-B*57:01 and abacavir hypersensitivity and HLA-B*15:02 and carbamazepine Stevens-Johnson syndrome/toxic epidermal necrolysis in Southeast Asian subjects. Future directions should include the collaboration of large international networks to develop and standardize in vivo diagnostic approaches, such as skin testing and patch testing, combined with ex vivo and in vitro laboratory approaches.

Purpose Severe skin reactions may complicate combination antiretroviral therapy (cART). Nevirapine is known to be associated with severe skin reactions, but there are conflicting data on risk factors in African patients. We reviewed cases of severe skin reactions admitted to a tertiary hospital in Cape Town, South Africa. We identified associations with severe skin reactions in patients on cART. Methods We described severe skin reaction cases in patients taking cART admitted to Groote Schuur Hospital in Cape Town, South Africa, between 2006 and 2012. We included those patients who developed a severe skin reaction within 120 days of cART initiation in a case–control analysis. We identified control patients matched on date of cART initiation and primary care facility by linkage with the Western Cape electronic provincial HIV database. We conducted a conditional (fixed effects) logistic regression modelling. Results We identified 169 severe skin reactions in patients on cART. The most common presentations were Stevens Johnson syndrome/toxic epidermal necrolysis (49%) and drug hypersensitivity syndrome (36%). One hundred forty-one patients were female, of which 27 were pregnant. Median duration of hospitalization was 12 days (interquartile range 8 to 19) and six patients died. We included 91 cases and 361 matched controls in the analysis. Severe skin reaction was associated with nevirapine exposure, adjusted odds ratio of 7.6 (95%CI 3.7 to 15.7) and with pregnancy, adjusted odds ratio 3.7 (95%CI 1.3 to 10.8) compared with men. Conclusions Severe skin reactions resulted in prolonged admission to hospital in this setting. We found that nevirapine use and pregnancy are independently associated with severe skin reaction. Copyright © 2016 John Wiley & Sons, Ltd.

Background The incidence of cutaneous adverse drug reactions (CADRs) to first-line antituberculosis drugs (FLTDs) is higher in HIV-tuberculosis coinfection. However, the utility of patch testing to identify the offending drug in this patient subgroup has been poorly studied. Objectives To identify drugs causing adverse drug reactions in patients with HIV-tuberculosis coinfection. Methods Fourteen consecutive patients underwent diagnostic work-up (patch testing followed by a skin prick test and an oral rechallenge) to pinpoint the offending drug after developing FLTD-associated CADR, which included drug rash with eosinophilia and systemic symptoms (n = 12), Stevens-Johnson syndrome (SJS, n = 1) and toxic epidermal necrolysis/SJS overlap (n = 1). A positive reaction to any of the three diagnostic modalities eliminated that drug from the regimen. Once patients were clinically stable postreaction, sequential and additive rechallenge with FLTDs was initiated. Results Eleven of the 14 participants with FLTD-associated CADR were HIV infected (median CD4 count 149 cells mm(-3) ). In this subgroup, patch testing resulted in generalized systemic reactions in 10 of 11 patients (91%). These included rash in 10 of 13 reactions (77%), eosinophilia in eight (62%), transaminitis in seven (54%) and fever in five (38%). Isoniazid caused six of 13 (46%) generalized systemic reactions, rifampicin four (31%), ethambutol two (15%) and pyrazinamide one reaction. Using the Common Terminology Criteria for Adverse Events, five of 13 reactions were mild, six were moderate and two were severe. There were no life-threatening or fatal reactions. Conclusions In HIV-infected persons with tuberculosis-associated CADR, although patch-testing reactions to FLTD are common and tend to be associated with systemic features, they are not life threatening or fatal. These data inform clinical practice in HIV-endemic settings.

Delayed immune-mediated adverse drug reactions (IM-ADRs) are defined as reactions occurring more than 6 hours after dosing. They include heterogeneous clinical phenotypes that are typically T-cell-mediated reactions with distinct mechanisms across a wide spectrum of severity from benign exanthems through to life-threatening cutaneous or organ-specific diseases. For mild reactions such as benign exanthem, considerations for delabeling are similar to immediate reactions and may include a graded or single-dose drug challenge with or without preceding skin or patch testing. Evaluation of challenging cases such as the patient who is on multiple drugs at the time a severe delayed IM-ADR occurs should prioritize clinical ascertainment of the most likely phenotype and implicated drug(s). Although not widely available and validated, procedures such as patch testing, delayed intradermal skin testing, and laboratory-based functional drug assays or genetic (human leukocyte antigen) testing may provide valuable information to further help risk stratify patients and identify the likely implicated and/or cross-reactive drug(s). The decision to use a drug challenge as a diagnostic or delabeling tool in a patient with a severe delayed IM-ADR should weigh the risk-benefit ratio, balancing the severity and priority for the treatment of the underlying, and the availability of alternative efficacious and safe treatments.

Effective treatment for drug-sensitive TB remains a long, multidrug endeavor. Therapeutic complexity is increased by HIV coinfection (>60% of incident TB cases are co-infected in HIV/TB endemic settings) and the growing burden of multi- and extremely drug-resistant TB (MDR- and XDR-TB). CADRs are common adverse reactions in both drug-sensitive and resistant anti-TB regimens, and the majorities are delayed T-cell-mediated reactions. Individual anti-TB drugs cause different CADR phenotypes of varying severity, while SCAR phenotypes such as DRESS, SJS/TEN, and LDE have been associated with many chemically different anti-TB drugs. The key management challenges include (1) multiple possible offending drugs, with a lack of accurate diagnostic testing, (2) high TB-related mortality with prolonged treatment interruptions, and (3) not unnecessarily excluding effective non-culprit anti-TB drugs in CADR patients. We discuss the spectrum of anti-TB drug-associated CADRs and offending drugs, as well as the pragmatic utility of drug provocation testing to identify culprit drugs and minimize treatment interruptions.

CADR is more common in HIV-infected persons, although the incidence is declining because of the new safer drugs and early initiation of antiretroviral therapy. The presentation and clinical course does not seem to differ from that in the general population. Antiretrovirals, antituberculosis drugs, and drugs for treating opportunistic infections are most commonly implicated. HIV-associated CADR poses major diagnostic and management challenges because of polypharmacy, overlapping drug toxicities, drug interactions, overlap of CADR with other diseases, and limited alternative drugs. We discuss pragmatic management strategies of HIV-associated CADR focusing on resource-limited settings, where HIV infection and associated CADR are most common.

Tattoos are becoming increasingly common. They have an impact on many aspects of clinician-patient interaction. Therefore, it is necessary for clinicians to have a basic knowledge of pertinent issues relating to tattoos. We provide a brief overview aimed at pointing the practising clinician who interacts with a tattooed person in the right direction. We discuss types of tattoos; their evolving epidemiology; the process of tattooing and variety of pigments used; medical application and relevance of tattoos; complications of tattooing; methods of removing tattoos, the efficacy of these methods and their associated complications; legislative framework guiding tattooing in South Africa and recent significant developments in the industry.

Adverse drug reactions (ADRs) are a significant health care burden. Immune-mediated adverse drug reactions (IM-ADRs) are responsible for one-fifth of ADRs but contribute a disproportionately high amount of that burden due to their severity. Variation in human leukocyte antigen ( HLA) genes has emerged as a potential preprescription screening strategy for the prevention of previously unpredictable IM-ADRs. Immunopharmacogenomics combines the disciplines of immunogenomics and pharmacogenomics and focuses on the effects of immune-specific variation on drug disposition and IM-ADRs. In this review, we present the latest evidence for HLA associations with IM-ADRs, ongoing research into biological mechanisms of IM-ADRs, and the translation of clinical actionable biomarkers for IM-ADRs, with a focus on T cell–mediated ADRs.

Sub-Saharan Africa bears the greatest burden of paediatric HIV disease. This atlas is the first of its kind with photographs of varying skin, systemic conditions and opportunistic infections in the HIV-infected paediatric patient. The aim of the atlas is to illustrate conditions which were captured among paediatric patients presenting to HIV clinics and wards in an African setting. Some of the conditions are commonly seen in HIV-infected children while some are not specific to HIV.

Immune-mediated adverse drug reactions (IM-ADRs) occur because of off-target interactions of medications with immune receptors and result in disproportionately high patient morbidity, mortality, and cost to drug delivery, development, and healthcare systems. IM-ADRs of greatest clinical relevance include Type I IgE-mediated anaphylaxis and delayed (Type IV) T cell–mediated pathologies across a spectrum of severity from benign exanthems to severe systemic, single-organ, and cutaneous pathologies such as drug reaction and eosinophilia and systemic symptoms, drug-induced liver disease, and Stevens-Johnson syndrome and toxic epidermal necrolysis. More recent discoveries of strong associations between human leukocyte antigen (HLA) genes and drug-specific T cell–mediated syndromes have not only provided pretreatment screening strategies for some drugs, but have also furthered our understanding of the immunopathogenesis of IM-ADR. Fundamental questions remain regarding the immunopathogenesis of T cell–mediated adverse drug reactions, including why, in most cases, only a small proportion of persons who carry a risk HLA gene will develop hypersensitivity to drug, why the clinical presentation of these syndromes varies widely, and how T cell immune responses are maintained for many years following drug exposure and resolution of clinical disease. In this chapter, we will review what is known about the immunopathogenesis of T cell–mediated adverse drug reactions with focus on drug- and syndrome-specific examples, how epidemiologic and mechanistic insights have been translated into clinical tests to prevent these syndromes, and future directions for basic science and clinical discovery in this field.

Background Isoniazid and ethionamide are important first- and second-line anti-TB drugs (FLDs and SLDs), respectively. Ethionamide is a structural analogue of isoniazid and the two drugs share other similarities, including their metabolism, therapeutic targets, hepato-toxicity patterns and drug resistance. As a result, there has always been concern about possible cross-reactivity between them. Methods Among 69 patients with drug rash with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) to FLDs, FLDs were stopped and SLDs added when the skin and laboratory parameters had settled. This was followed by sequential and additive rechallenge with FLDs. We report 25 consecutive cases that developed confirmed cutaneous adverse drug reactions (CADRs) to isoniazid or ethionamide used as FLD and SLD, respectively. Results Sixty-nine participants who developed CADRs on FLDs were enrolled in the study. Twenty developed a rechallenge reaction to isoniazid and five reacted to ethionamide. Four of the 20 isoniazid cases were patch test positive, 3/20 were skin prick test positive and 13/20 reacted to oral rechallenge. All seven cases that were patch and skin prick test positive were associated with systemic reactions. Twenty of the 25 cases had DRESS and 5 had SJS/TEN. Twenty-three of the 25 cases with rechallenge reactions were HIV infected. Importantly, none of the cases that reacted to ethionamide during the rechallenge reacted to isoniazid and none who subsequently reacted to isoniazid reacted to ethionamide. Conclusions Our findings strongly suggest that the risk of cross-reactivity of isoniazid and ethionamide in DRESS syndrome and SJS/TEN is low. These findings have implications for clinical management.

Background Skin lesions are common in advanced HIV infection and are sometimes caused by serious diseases like systemic mycoses (SM). AIDS-related SM endemic to Western Cape, South Africa, include emergomycosis (formerly disseminated emmonsiosis), histoplasmosis, and sporotrichosis. We previously reported that 95% of patients with AIDS-related emergomycosis had skin lesions, although these were frequently overlooked or misdiagnosed clinically. Prospective studies are needed to characterize skin lesions of SM in South Africa and to help distinguish these from common HIV-related dermatoses. Methods We prospectively enrolled HIV-infected adult patients living in Western Cape, South Africa, with CD4 counts ≤100 cells/μL and widespread skin lesions present ≤6 months that were deemed clinically compatible with SM. We obtained skin biopsies for histopathology and fungal culture and collected epidemiological and clinical data. Results Of 34 patients enrolled and in whom a diagnosis could be made, 25 had proven SM: 14 had emergomycosis, and 3 each had histoplasmosis and sporotrichosis; for 5 additional patients, the fungal species could not be identified. Antiretroviral therapy (ART) had been initiated in the preceding 4 weeks for 11/25 (44%) patients with SM (vs no patients without SM). Plaques and scale crust occurred more frequently in patients with SM (96% vs 25%, P = .0002; and 67% vs 13%, P = .01, respectively). Conclusions Recent ART initiation and presence of plaques or scale crust should make clinicians consider SM in patients with advanced HIV infection in this geographic area. Clinical overlap between SM and other dermatoses makes early skin biopsy critical for timely diagnosis and treatment.

Elimination of a rifamycin from the treatment regimen for tuberculosis negatively impacts outcomes. Cross-reactivity between the rifamycins after drug eruptions is unclear. We report 6 consecutive human immunodeficiency virus-infected patients with rifampicin-associated drug rash with eosinophilia and systemic symptoms (DRESS) syndrome confirmed on diagnostic rechallenge. The patients subsequently tolerated rifabutin. These data inform clinical management of tuberculosis-associated drug reactions.

Increased risk of tuberculosis (TB) associated with HIV-1 infection is primarily attributed to deficient T helper (Th)1 immune responses, but most people with active TB have robust Th1 responses, indicating that these are not sufficient to protect against disease. Recent findings suggest that favourable outcomes following Mycobacterium tuberculosis infection arise from finely balanced inflammatory and regulatory pathways, achieving pathogen control without immunopathology. We hypothesised that HIV-1 and antiretroviral therapy (ART) exert widespread changes to cell mediated immunity, which may compromise the optimal host protective response to TB and provide novel insights into the correlates of immune protection and pathogenesis. We sought to define these effects in patients with active TB by transcriptional profiling of tuberculin skin tests (TST) to make comprehensive molecular level assessments of in vivo human immune responses at the site of a standardised mycobacterial challenge. We showed that the TST transcriptome accurately reflects the molecular pathology at the site of human pulmonary TB, and used this approach to investigate immune dysregulation in HIV-1/TB co-infected patients with distinct clinical phenotypes associated with TST reactivity or anergy and unmasking TB immune reconstitution inflammatory syndrome (IRIS) after initiation of ART. HIV-1 infected patients with positive TSTs exhibited preserved Th1 responses but deficient immunoregulatory IL10-inducible responses. Those with clinically negative TSTs revealed profound anergy of innate as well as adaptive immune responses, except for preservation of type 1 interferon activity, implicated in impaired anti-mycobacterial immunity. Patients with unmasking TB IRIS showed recovery of Th1 immunity to normal levels, but exaggerated Th2-associated responses specifically. These mechanisms of immune dysregulation were localised to the tissue microenvironment and not evident in peripheral blood. TST molecular profiling categorised different mechanisms of immunological dysfunction in HIV-1 infection beyond the effects on CD4 T cells, each associated with increased risk of TB disease and amenable to host-directed therapies.

BACKGROUND Data regarding outcomes of tuberculosis (TB) associated cutaneous adverse drug reactions (CADR) are limited. The re-introduction of first-line anti-tuberculosis drugs after CADR is controversial and management poorly defined. METHODS We retrospectively reviewed the records of 298 patients with CADR admitted to a tertiary dermatology ward in Cape Town, South Africa. RESULTS TB-associated CADR was diagnosed in 65 of 298 patients. Of these, 60/65 (92%) were human immunodeficiency virus (HIV) infected (median CD4 count 107 cells/mm (3)). Anti-tuberculosis drugs were reintroduced in 46/65 (71%) patients, of whom 23/46 (50%) developed re-introduction reactions. The most frequent re-introduction reactions were itch in 11/23 (48%) and hepatitis in 9/23 (39%) patients. Of the 23 re-introduction reactions, 13 (57%) were mild, six (26%) moderate and four (26%) severe. Among those with reintroduction reactions, rifampicin (RMP) was the offending drug in 13/23 (57%), isoniazid in 5/23(22%), pyrazinamide in 3/23 (13%), and ethambutol, streptomycin and ofloxacin each in 1/23 (4%) cases. Lack of previous TB treatment and re-challenge with RMP were independently associated with the likelihood of reintroduction reactions. CONCLUSIONS In this high TB burden setting, although re-introduction reactions are common, the majority are non-life-threatening. All first-line anti-tuberculosis drugs can cause CADR, and RMP is more commonly implicated than previously reported. These data guide the management of anti-tuberculosis drug-associated CADR in high HIV prevalence settings.

Background Folliculitis keloidalis nuchae (FKN), characterized by nucheal pimples and keloids, has a predilection for curly African hair. The disease is 10 times more common in males than females. The aim of this study was to investigate determinants of FKN in males. Methods Factors associated with the presence of FKN were investigated from two cross-sectional studies involving 1042 children and 874 adults, respectively. All participants had given informed consent. A clinical diagnosis of FKN was made only if nucheal keloidal papules (or plaques) were present. Multiple logistic regression was used to assess the relationship between FKN and specific characteristics in male participants. Results The odds ratio (OR) for FKN in males was higher in the adult than the child study [OR = 7.26, 95% confidence interval (CI) 3.13–16.88; P 50 years (OR = 2.44, 95% CI 0.75–7.89; P = 0.14) but significantly higher in those aged >25–50 years (OR = 5.75, 95% CI 2.67–12.64; P

The tuberculin skin test (TST) is a model of integrated innate and adaptive human immune responses to Mycobacterium tuberculosis, but the component processes that are involved in this model have not previously been defined in vivo. We used transcriptional profiling to study these responses within the TST at molecular and system levels. Skin biopsies from TST injection sites were examined in subjects classified as TST(+) or TST(-) by clinical and histological criteria. Genome-wide expression arrays showed evolution of immune responses reflecting T-cell activation and recruitment with uniquely Th1-polarized responses and cytotoxic T cells (CTLs). In addition, distinct innate immune and IFN-γ-stimulated gene expression signatures were identified, under the regulation of NF-κB and STAT1 transcriptional control. These were highly enriched for chemokines and MHC class II molecules providing a potential mechanism for paracrine amplification of inflammatory responses in the TST, by supporting cellular recruitment and enhancing antigen presentation. The same repertoire of innate and adaptive immune responses was evident in TST(+) and TST(-) subjects alike, clinically positive TSTs being distinguished only by quantitatively greater differences. These data provide new insights into complex multifaceted responses within the TST, with much greater sensitivity than previous clinical or histological assessments.

Rationale Striking class I HLA risk associations and CD8+ T cell dependency have been described for both Stevens-Johnson Syndrome/toxic epidermal necrolysis (SJS/TEN) and abacavir hypersensitivity (AHS). However, distinct clinical phenotypes and positive predictive values (55% for HLA-B*57:01 restricted AHS and 97%) in blister fluid and skin. In contrast, for AHS, abacavir responsive CD8+ T cells with shared TCR clonotypes were isolated from the peripheral blood and positive patch tests that were polyclonal. Conclusions Single cell approaches that define the signatures of drug-specific T cells in the skin and peripheral blood highlight mechanistic differences between HLA class I restricted drug hypersensitivity syndromes and will help drive the development of targeted therapeutics and screening approaches.

Increased risk of tuberculosis (TB) associated with HIV-1 infection is primarily attributed to deficient T helper (Th)1 immune responses, but most people with active TB have robust Th1 responses, indicating that these are not sufficient to protect against disease. Recent findings suggest that favourable outcomes following Mycobacterium tuberculosis infection arise from finely balanced inflammatory and regulatory pathways, achieving pathogen control without immunopathology. We hypothesised that HIV-1 and antiretroviral therapy (ART) exert widespread changes to cell mediated immunity, which may compromise the optimal host protective response to TB and provide novel insights into the correlates of immune protection and pathogenesis. We sought to define these effects in patients with active TB by transcriptional profiling of tuberculin skin tests (TST) to make comprehensive molecular level assessments of in vivo human immune responses at the site of a standardised mycobacterial challenge. We showed that the TST transcriptome accurately reflects the molecular pathology at the site of human pulmonary TB, and used this approach to investigate immune dysregulation in HIV-1/TB co-infected patients with distinct clinical phenotypes associated with TST reactivity or anergy and unmasking TB immune reconstitution inflammatory syndrome (IRIS) after initiation of ART. HIV-1 infected patients with positive TSTs exhibited preserved Th1 responses but deficient immunoregulatory IL10-inducible responses. Those with clinically negative TSTs revealed profound anergy of innate as well as adaptive immune responses, except for preservation of type 1 interferon activity, implicated in impaired anti-mycobacterial immunity. Patients with unmasking TB IRIS showed recovery of Th1 immunity to normal levels, but exaggerated Th2-associated responses specifically. These mechanisms of immune dysregulation were localised to the tissue microenvironment and not evident in peripheral blood. TST molecular profiling categorised different mechanisms of immunological dysfunction in HIV-1 infection beyond the effects on CD4 T cells, each associated with increased risk of TB disease and amenable to host-directed therapies., Author Summary HIV-1 infected people have substantially increased risk of tuberculosis (TB) leading to a large burden of disease worldwide. We aimed to investigate how HIV-1 causes this effect by altering human immune responses. We measured the products of all immune genes at injection sites of sterilized TB under the skin, in order to look for differences between TB patients with and without HIV-1. We found that the predominant effect of early HIV-1 infection was to diminish a component of immune responses that contributes to prevention of harmful inflammation. In more advanced HIV-1, we found almost complete absence of any immune response to TB except for immune activity which is normally part of our defence against viruses, but may also weaken immune protection against TB. In some patients, TB becomes apparent after starting treatment for HIV-1. In these patients we found that most immune responses had recovered to normal levels, but that one type of response sometimes associated with asthma and allergies was exaggerated. Our findings provide new insights into how HIV-1 can affect immune responses and changes to the immune system that are associated with risk of TB, which will inform the development of new strategies to improve protective immunity.

A 31-year old HIV-infected African woman on nevirapine, tenofovir and lamivudine for more than 4 years presented with an 8-day history of symptoms and signs of Stevens-Johnson syndrome. She was on no other medication. Her viral load was undetectable and she had maintained a CD4 count of between 356 and 387cells/mm3 in the preceding 2½ years. She missed her antiretrovirals 10 days before the onset of her symptoms and subsequently doubled her daily dose the following day. She had been on no other medication in the preceding 8 weeks.Her ARVs were stopped and she fully re-epithelialized with the exception of the lips, over the following 10 days. She was started on a daily single tablet of Odimune® (a fixed drug combination antiretroviral containing tenofovir, emtricitabine and efavirenz).Nevirapine is the most common offender in cases of antiretroviral-associated SJS in published literature. Lamivudine is very rarely implicated while there are no similar reports with tenofovir. We concluded that nevirapine was by far the most likely offender in this case. Nevirapine toxicity is associated with high CD4 counts, undetectable viral load and high drug plasma level. We postulate that the sudden increase of the plasma levels of nevirapine in a patient with a high CD4 count and undetectable viral load created a perfect storm for the development of SJS in our patient, who had been on the NVP-containing regimen for many years.Clinicians should be aware that severe adverse drug reactions are dynamic and can occur even when the drug has been in use for a long time.

The first 54 cases are reported of disseminated emmonsiosis, a newly described endemic mycosis in South Africa. Most patients were profoundly immunocompromised. Disease most commonly involved the skin and lungs. Nearly half of all patients died, often undiagnosed.Methods.aEuro integral We performed a multicenter, retrospective chart review of laboratory-confirmed cases of emmonsiosis diagnosed across South Africa from January 2008 through February 2015. Results.aEuro integral Fifty-four patients were diagnosed in 5/9 provinces. Fifty-one patients (94%) were human immunodeficiency virus coinfected (median CD4 count 16 cells/A mu L [interquartile range, 6-40]). In 12 (24%) of these, antiretroviral therapy had been initiated in the preceding 2 months. All patients had disseminated disease, most commonly involving skin (n = 50/52, 96%) and lung (n = 42/48, 88%). Yeasts were visualized on histopathologic examination of skin (n = 34/37), respiratory tissue (n = 2/4), brain (n = 1/1), liver (n = 1/2), and bone marrow (n = 1/15). Emmonsia sp. was cultured from skin biopsy (n = 20/28), mycobacterial/fungal and aerobic blood culture (n = 15/25 and n = 9/37, respectively), bone marrow (n = 12/14), lung (n = 1/1), lymph node (n = 1/1), and brain (n = 1/1). Twenty-four of 34 patients (71%) treated with amphotericin B deoxycholate, 4/12 (33%) treated with a triazole alone, and none of 8 (0%) who received no antifungals survived. Twenty-six patients (48%) died, half undiagnosed. Conclusions.aEuro integral Disseminated emmonsiosis is more widespread in South Africa and carries a higher case fatality rate than previously appreciated. Cutaneous involvement is near universal, and skin biopsy can be used to diagnose the majority of patients.

The immune reconstitution inflammatory syndrome (IRIS) represents a diverse range of immunopathologic reactions resulting in clinical deterioration that may occur as immune function is partially restored in HIV-infected patients receiving highly active antiretroviral therapy. Approximately half of IRIS events are dermatologic, and dermatologic IRIS is described in relation to a wide range of conditions, the commonest being herpes zoster and herpes simplex. Most cases of IRIS result in mild and moderate symptoms, but non-dermatologic manifestations related to IRIS have resulted in death. This article covers certain general issues related to IRIS and then focuses on the spectrum of dermatologic manifestations.

Sir, Tuberculosis-associated adverse drug reactions (ADRs) result in an interruption and change of treatment, both impacting on treatment failure, the development of drug resistance, relapse and the transmission of disease.1 The threat of transmission makes prompt resumption of therapy necessary, but the limited number of effective antituberculosis drugs complicates management. The spectrum of severe tuberculosis-associated cutaneous ADRs is wide and includes Stevens–Johnson syndrome, drug hypersensitivity syndrome and lichenoid drug reactions (LDRs).2 In all, with the exception of LDRs, acute clinical or laboratory markers enable early detection and withdrawal of the offending drug following drug rechallenge.3 We present a case of severe LDR related to antituberculosis drugs in which the offending drug could not be definitively identified and therapy was continued successfully under the cover of topical steroids and phototherapy. A 39-year-old HIV-infected man presented with erythroderma 3 months after starting isoniazid, rifampicin, pyrazinamide and ethambutol for pulmonary tuberculosis and co-trimoxazole for Pneumocystis jiroveci prophylaxis. He had a CD4 count of 8 cells/mm3 and was taking efavirenz, lamivudine and stavudine, all of which were started after the onset of the rash. A skin biopsy showed a lichenoid reaction with eosinophils and apoptotic keratinocytes compatible with LDR. Antituberculosis drugs and co-trimoxazole were stopped and he was started on topical clobetasol (Dovate™) daily. The rash settled with residual pigmentation and ofloxacin, streptomycin and ethionamide were initiated.1 Rifampicin was then reintroduced with escalating doses over 4 days without a clinically evident reaction. Ethambutol, pyrazinamide and isoniazid were not reintroduced on the assumption that they were the likeliest offenders. He was discharged from hospital on the four antituberculosis drugs. Six weeks later he presented again with a 3 week history of the same rash. In the meantime his sputum reverted to culture-negative, and his tuberculosis symptoms and radiological features had improved. We thought rifampicin was the likeliest offender, but decided not to replace it with another second-line drug or rechallenge with the three first-line drugs initially omitted. This was informed by the patient's unwillingness to restart the rechallenge process, the clinical improvement and the delay in clinical manifestation of LDR, possibly due to topical steroids. We continued treatment under cover of clobetasol. The rash improved and he was discharged from hospital. He presented again 3 weeks later with worsening hyperpigmentation, depigmentation and diffuse alopecia, despite topical steroids. We introduced thrice weekly bath psoralen and ultraviolet A (PUVA). His skin gradually improved; however, 1 month later he developed photo-distributed rash with painful fissures, which we attributed to excessive sun exposure (see Figure 1). PUVA was suspended for 1 week and he was advised to minimize sun exposure. Sunscreen was prescribed, and he was advised to wear a hat and gloves on the day he received psoralen, a potent photosensitizer. He completed 12 months of treatment, and continued steroids and PUVA for 3 months thereafter. His skin has clinically improved with only residual hyperpigmentation and leucoderma (see Figure 1). Figure 1. (a and b) Lichenoid drug reaction showing depigmentation, hyperpigmentation and fissuring. (c) Clinically improved skin 1 week after completing antituberculosis therapy. LDR presents as purple itchy papules becoming confluent and hyperpigmented with continuing exposure to the offending drug. The interval between initiating the drug and the rash ranges from days to years, with most cases occurring within months. On withdrawing the drug, the lesions resolve with persistent hyperpigmentation, often lasting for many years.4 The lack of acute markers, insidious onset of the rash, and varying intervals between drug initiation and a clinically detectable rash make it difficult to establish a temporal relationship with the drug and ascribe causality in LDR. This is more so in patients receiving multiple drugs. The limited number of effective antituberculosis drugs, the cessation of which is associated with a higher mortality, increases risk of drug resistance, longer duration of therapy and public health concerns, make it necessary to balance the interruption of therapy against treating through the ADRs.1,5 PUVA is used to treat a wide variety of inflammatory dermatological conditions, such as scleroderma, lichen planus, psoriasis, vitiligo, cutaneous T cell lymphoma and atopic dermatitis. It is also effective for pruritus associated with systemic disease. Psoralen is administered orally or topically by soaking in bathwater, followed by irradiation. The first-line therapy generally used for LDRs is high-potency topical steroids, although there are no clinical trials supporting their use. There are better data supporting the use of acitretin, systemic steroids and other immunosuppressants.6 However, considering our patient's marked immunosuppression and concurrent tuberculosis, we decided to use only topical steroids. This case illustrates practical dilemmas in managing tuberculosis-associated ADRs. Should suboptimal treatment be used or should a potentially life-threatening therapy be continued despite serious side effects? We decided to continue treatment and manage the side effects, as the alternative would likely result in a poorer outcome. Phototherapy, in combination with topical steroids, is an option in the management of LDRs when the offending drug cannot be identified. Written permission was given by the patient to publish the case and images.

Sub-Saharan Africa is the epicenter of the HIV pandemic and HIV-infected people are more susceptible to inflammatory dermatoses, infections, and drug eruptions. Many of the drugs used for HIV-associated opportunistic infections are associated with a higher incidence of drug-related toxicities and drug interactions. This article discusses the epidemiology, pharmacogenetics, and clinical features of idiosyncratic drug reactions in HIV-infected Africans. Special considerations in this population, including immune reconstitution inflammatory syndrome, multiple drug hypersensitivity syndrome, drug reactions in pregnancy, drug rechallenge in lichenoid drug eruptions, and anxiety/depression after cutaneous adverse drug reactions, are also briefly discussed.