Rannakoe Lehloenya

Drug-associated adverse events and their relationship with outcomes in patients receiving treatment for extensively drug-resistant tuberculosis in South Africa.

Background Treatment-related outcomes in patients with extensively drug-resistant tuberculosis (XDR-TB) are poor. However, data about the type, frequency and severity of presumed drug-associated adverse events (AEs) and their association with treatment-related outcomes in patients with XDR-TB are scarce. Methods Case records of 115 South-African XDR-TB patients were retrospectively reviewed by a trained researcher. AEs were estimated and graded according to severity [grade 0 = none; grade 1–2 = mild to moderate; and grade 3–5 = severe (drug stopped, life-threatening or death)]. Findings 161 AEs were experienced by 67/115(58%) patients: 23/67(34%) required modification of treatment, the offending drug was discontinued in 19/67(28%), reactions were life-threatening in 2/67(3.0%), and 6/67(9.0%) died. ∼50% of the patients were still on treatment at the time of data capture. Sputum culture-conversion was less likely in those with severe (grade 3–5) vs. grade 0–2 AEs [2/27(7%) vs. 24/88(27%); p = 0.02]. The type, frequency and severity of AEs was similar in HIV-infected and uninfected patients. Capreomycin, which was empirically administered in most cases, was withdrawn in 14/104(14%) patients, implicated in (14/34) 41% of the total drug withdrawals, and was associated with all 6 deaths in the severe AE group (renal failure in five patients and hypokalemia in one patient). Conclusion Drug-associated AEs occur commonly with XDR-TB treatment, are often severe, frequently interrupt therapy, and negatively impact on culture conversion outcomes. These preliminary data inform on the need for standardised strategies (including pre-treatment counselling, early detection, monitoring, and follow-up) and less toxic drugs to optimally manage patients with XDR-TB.

Clinical Characteristics, Diagnosis, Management, and Outcomes of Disseminated Emmonsiosis: A Retrospective Case Series

BACKGROUND We describe the geographic distribution, clinical characteristics, and management of patients with disease caused by Emmonsia sp., a novel dimorphic fungal pathogen recently described in South Africa. METHODS We performed a multicenter, retrospective chart review of laboratory-confirmed cases of emmonsiosis diagnosed across South Africa from January 2008 through February 2015. RESULTS Fifty-four patients were diagnosed in 5/9 provinces. Fifty-one patients (94%) were human immunodeficiency virus coinfected (median CD4 count 16 cells/µL [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 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.

Cutaneous adverse drug reactions to anti-tuberculosis drugs: state of the art and into the future

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.

Transcriptional profiling of innate and adaptive human immune responses to mycobacteria in the tuberculin skin test

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.

Severe Delayed Cutaneous and Systemic Reactions to Drugs: A Global Perspective on the Science and Art of Current Practice

Most immune-mediated adverse drug reactions (IM-ADRs) involve the skin, and many have additional systemic features. Severe cutaneous adverse drug reactions (SCARs) are an uncommon, potentially life-threatening, and challenging subgroup 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, 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 comorbid 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 comorbid disease necessitating ongoing treatments, and cost considerations. In this review, we update the basic and clinical science of SCAR diagnosis and management.

Severe recurrence of drug rash with eosinophilia and systemic symptoms syndrome secondary to rifampicin patch testing in a human immunodeficiency virus-infected man.

Human immunodeficiency virus (HIV)-infected persons are more susceptible to tuberculosis and cutaneous adverse drug reactions (CADRs) to antituberculosis drugs. The eruptions range from mild to life-threatening, and may be associated with interruption of therapy. The limited number of effective first-line antituberculosis drugs complicates the management of HIV-infected persons who develop tuberculosis-associated CADRs. Second-line drugs have additional toxicities and are less effective. Thus, it is sometimes necessary to rechallenge first-line drugs to establish causality and eliminate the offending drug(s) from the treatment regimen. This can be done either in vitro or in vivo. The in vitro methods are not readily available, and are still considered to be experimental (1).

SJS/TEN 2017: Building Multidisciplinary Networks to Drive Science and Translation

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 to 5 per 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 before 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.

AIDS-Related Endemic Mycoses in Western Cape, South Africa, and Clinical Mimics: A Cross-Sectional Study of Adults With Advanced HIV and Recent-Onset, Widespread Skin Lesions

Abstract 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.

Factors associated with increased mortality in a predominantly HIV-infected population with Stevens Johnson syndrome and toxic epidermal necrolysis.

Introduction Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening drug reactions with a higher incidence in HIV-infected persons. SJS/TEN are associated with skin and mucosal failure, predisposing to systemic bacterial infection (BSI), a major cause of death. There are limited data on risk factors associated with BSI and and mortality in HIV-infected people with SJS/TEN. Methods We conducted a retrospective study of patients admitted to a university hospital with SJS/TEN over a 3 year period. We evaluated their underlying illnesses, eliciting drugs, predictive value of bacterial skin cultures and other factors associated with mortality and BSI in a predominantly HIV-infected population by comparing characteristics of the patients who demised and those who survived. Results We admitted 86 cases during the study period and 67/86(78%) were HIV-infected. Tuberculosis was the commonest co-morbidity, diagnosed in 12/86(14%) cases. Skin cultures correlated with BSI by the same organism in 7/64(11%) cases and 6/7 were Gram-negative. Two of the 8 cases of Gram-negative BSI had an associated Gram-negative skin culture, although not always the same organism. All 8 fatalities had >30% epidermal detachment, 7 were HIV-infected, 6 died of BSI and 6 had tuberculosis. Conclusions Having >30% epidermal detachment in SJS/TEN carries an increased risk of BSI and mortality. Tuberculosis and BSI are associated with higher risk of death in SJS/TEN. Our data suggests there may be an association between Gram-negative BSI and Gram-negative skin infection.

Annular erythema and photosensitivity as manifestations of efavirenz-induced cutaneous reactions: a review of five consecutive cases

OBJECTIVES In HIV-infected persons, a rash is the most common manifestation of drug hypersensitivity reactions. Non-nucleotide reverse transcriptase inhibitors are a major cause of cutaneous reactions. While the characteristics of nevirapine-associated cutaneous adverse drug reactions (CADRs) have been well described, there are limited data on efavirenz-associated CADRs. The objective of this study was to characterize the clinical features of consecutive cases of efavirenz-associated CADRs in a single referral centre diagnosed over a 3 year period. METHODS We retrospectively reviewed the clinical records of 231 patients admitted with CADRs to a tertiary dermatology ward in Cape Town, South Africa. RESULTS In 42/231(18%) cases, there had been exposure to efavirenz in the preceding 8 weeks. Of these, 5/42 (12%) patients were diagnosed with probable efavirenz-associated CADRs based on the Naranjo score. The median exposure to efavirenz before the onset of the rash was 12 days (range 2-48). All the patients were female, with a median age of 31 years and a median CD4 cell count of 300 cells/mm(3) (range 81-887). Four had a photo-distributed eruption and one had a confluent indurated erythema affecting the face, trunk and limbs. In three out of five cases, there were annular plaques with raised erythematous edges and dusky centres, which were photo-distributed. Two patients had a mild transaminitis and another a mild eosinophilia. Histological features were non-specific, with perivascular lymphocytes the only consistent feature. In all five cases, efavirenz was withdrawn and potent topical steroid was the only CADR-specific intervention. The eruptions resolved on discharge from hospital, with no sequelae except for residual post-inflammatory hyperpigmentation. CONCLUSIONS Photo-distribution and annular erythema should alert clinicians to the possibility of efavirenz-associated CADRs.