HIV and skin infections.

HIV infection alters the skin microbiome and predisposes to a wide range of cutaneous infections, from atypical presentations of common skin infections to severe disseminated infections involving the skin that are AIDS-defining illnesses. Bacterial infection of the skin, most commonly caused by Staphylococcus aureus, occurs frequently and can result in bacteremia. Nontuberculous mycobacterial infections that are usually localized to the skin may disseminate, and guidance on the treatment of these infections is limited. Herpes simplex can be severe, and less common presentations such as herpetic sycosis and herpes vegetans have been reported. Severe herpes zoster, including disseminated infection, requires intravenous antiviral treatment. Viral warts can be particularly difficult to treat, and in atypical or treatment-resistant cases a biopsy should be considered. Superficial candidosis occurs very commonly in people living with HIV, and antifungal resistance is an increasing problem in non-albicans Candida species. Systemic infections carry a poor prognosis. In tropical settings the endemic mycoses including histoplasmosis are a problem for people living with HIV, and opportunistic infections can affect those with advanced HIV in all parts of the world. Most cutaneous infections can develop or worsen as a result of immune reconstitution in the weeks to months after starting antiretroviral therapy. Direct microscopic examination of clinical material can facilitate rapid diagnosis and treatment initiation, although culture is important to provide microbiological confirmation and guide treatment.

Long-term management options for sea urchin injury: a case series.

In the UK, sea urchin-related injuries (SUIs) most commonly present in returning travellers. Delayed complications mainly affect the skin but nerves, tendons, joints and bones may also be involved. The management of chronic reactions may be challenging and a variety of approaches have been described. Surgical measures are often undertaken, particularly when retained spines are suspected. We demonstrate, through three cases presenting in the UK with chronic SUIs, that conservative management, surgery and intralesional corticosteroids may all be associated with satisfactory outcomes. Management options should consider the presence of retained spines, injury site, symptoms and importantly, patient preference.

Regulatory T cells in erythema nodosum leprosum maintain anti-inflammatory function.

BACKGROUND: The numbers of circulating regulatory T cells (Tregs) are increased in lepromatous leprosy (LL) but reduced in erythema nodosum leprosum (ENL), the inflammatory complication of LL. It is unclear whether the suppressive function of Tregs is intact in both these conditions. METHODS: A longitudinal study recruited participants at ALERT Hospital, Ethiopia. Peripheral blood samples were obtained before and after 24 weeks of prednisolone treatment for ENL and multidrug therapy (MDT) for participants with LL. We evaluated the suppressive function of Tregs in the peripheral blood mononuclear cells (PBMCs) of participants with LL and ENL by analysis of TNFα, IFNγ and IL-10 responses to Mycobacterium leprae (M. leprae) stimulation before and after depletion of CD25+ cells. RESULTS: 30 LL participants with ENL and 30 LL participants without ENL were recruited. The depletion of CD25+ cells from PBMCs was associated with enhanced TNFα and IFNγ responses to M. leprae stimulation before and after 24 weeks treatment of LL with MDT and of ENL with prednisolone. The addition of autologous CD25+ cells to CD25+ depleted PBMCs abolished these responses. In both non-reactional LL and ENL groups mitogen (PHA)-induced TNFα and IFNγ responses were not affected by depletion of CD25+ cells either before or after treatment. Depleting CD25+ cells did not affect the IL-10 response to M. leprae before and after 24 weeks of MDT in participants with LL. However, depletion of CD25+ cells was associated with an enhanced IL-10 response on stimulation with M. leprae in untreated participants with ENL and reduced IL-10 responses in treated individuals with ENL. The enhanced IL-10 in untreated ENL and the reduced IL-10 response in prednisolone treated individuals with ENL was abolished by addition of autologous CD25+ cells. CONCLUSION: The findings support the hypothesis that the impaired cell-mediated immune response in individuals with LL is M. leprae antigen specific and the unresponsiveness can be reversed by depleting CD25+ cells. Our results suggest that the suppressive function of Tregs in ENL is intact despite ENL being associated with reduced numbers of Tregs. The lack of difference in IL-10 response in control PBMCs and CD25+ depleted PBMCs in individuals with LL and the increased IL-10 response following the depletion of CD25+ cells in individuals with untreated ENL suggest that the mechanism of immune regulation by Tregs in leprosy appears independent of IL-10 or that other cells may be responsible for IL-10 production in leprosy. The present findings highlight mechanisms of T cell regulation in LL and ENL and provide insights into the control of peripheral immune tolerance, identifying Tregs as a potential therapeutic target.

Leprosy-an unusual cause of a suspicious nodule on mammography.

A routine mammogram identified changes thought to be due to a lymph node, which was confirmed on biopsy. The lymph node was infiltrated with macrophages and showed fragmented acid-fast bacilli. The patient had been treated for leprosy some years before and was still taking thalidomide for erythema nodosum leprosum. Leprosy-associated lymphadenopathy may be identified on routine breast screening.

Leg ulceration due to cutaneous melioidosis in a returning traveller.

A 26-year-old man, returned to the UK having travelled extensively in Asia. He was referred with a 3-month history of distal leg ulceration following an insect bite while in Thailand. Despite multiple courses of oral antibiotics, he developed two adjacent ulcers. A wound swab isolated an organism identified as Burkholderia thailandensis The histology of the skin biopsy was non-specific. A diagnosis of cutaneous melioidosis was made, based on clinical and microbiological grounds. The ulcers re-epithelialised on completion of intravenous ceftazidime followed by 3 months of high dose co-trimoxazole and wound care. Many clinical microbiology laboratories have limited diagnostics for security-related organisms, with the result that B. pseudomallei, the causative bacterium of melioidosis, may be misidentified. This case highlights the importance of maintaining high levels of clinical suspicion and close microbiological liaison in individuals returning from South-East Asia and northern Australia with such symptoms.

Biologics in Leprosy: A Systematic Review and Case Report.

Tumor necrosis factor (TNF)-α inhibitors increase susceptibility to tuberculosis, but the effect of biologics on susceptibility to leprosy has not been described. Moreover, biologics may play a role in treating erythema nodosum leprosum (ENL). The objectives of this systematic review were to determine whether the development of clinical leprosy is increased in patients being treated with biologics and to assess the use of biologics in treating leprosy reactions. A systematic literature review was completed of patients with leprosy who received treatment with biologics either before or after a diagnosis of leprosy was confirmed. All studies and case reports were included for qualitative evaluation. The search yielded 10 cases (including one duplicate publication) of leprosy diagnosed after initiation of TNF-α inhibitors and four case reports of refractory ENL successfully treated with infliximab or etanercept. An unpublished case of persistent ENL responsive to infliximab is also presented. These data demonstrate that the use of TNF-α inhibitors may be a risk factor for developing leprosy or reactivating subclinical infections. Leprosy can present with skin lesions and arthritis, so leprosy should be considered in patients presenting with these signs before starting treatment with these agents. Leprosy should be considered in patients who develop worsening eruptions and neurologic symptoms during treatment with TNF-α inhibitors. Finally, TNF-α inhibitors appear effective in some cases of refractory ENL.

The Effects of Prednisolone Treatment on Cytokine Expression in Patients with Erythema Nodosum Leprosum Reactions.

Erythema nodosum leprosum (ENL) is a systemic inflammatory complication occurring mainly in patients with lepromatous leprosy (LL) and borderline lepromatous leprosy. Prednisolone is widely used for treatment of ENL reactions but clinical improvement varies. However, there is little good in vivo data as to the effect of prednisolone treatment on the pro-inflammatory cytokines in patients with ENL reactions. As a result, treatment and management of reactional and post-reactional episodes of ENL often pose a therapeutic challenge. We investigated the effect of prednisolone treatment on the inflammatory cytokines TNF, IFN-γ, IL-1ß, IL-6, and IL-17 and the regulatory cytokines IL-10 and TGF-ß in the skin lesion and blood of patients with ENL and compared with non-reactional LL patient controls. A case-control study was employed to recruit 30 patients with ENL and 30 non-reactional LL patient controls at ALERT Hospital, Ethiopia. Blood and skin biopsy samples were obtained from each patient before and after prednisolone treatment. Peripheral blood mononuclear cells from patients with ENL cases and LL controls were cultured with M. leprae whole-cell sonicates (MLWCS), phytohemagglutinin or no stimulation for 6 days. The supernatants were assessed with the enzyme-linked immunosorbent assay for inflammatory and regulatory cytokines. For cytokine gene expression, mRNA was isolated from whole blood and skin lesions and then reverse transcribed into cDNA. The mRNA gene expression was quantified on a Light Cycler using real-time PCR assays specific to TNF, IFN-γ, IL-ß, TGF-ß, IL-17A, IL-6, IL-8, and IL-10. The ex vivo production of the cytokines: TNF, IFN-γ, IL-1ß, and IL-17A was significantly increased in untreated patients with ENL. However, IL-10 production was significantly lower in untreated patients with ENL and significantly increased after treatment. The ex vivo production of IL-6 and IL-8 in patients with ENL did not show statistically significant differences before and after prednisolone treatment. The mRNA expression in blood and skin lesion for TNF, IFN-γ, IL-1ß, IL-6, and IL-17A significantly reduced in patients with ENL after treatment, while mRNA expression for IL-10 and TGF-ß was significantly increased both in blood and skin lesion after treatment. This is the first study examining the effect of prednisolone on the kinetics of inflammatory and regulatory cytokines in patients with ENL reactions before and after prednisolone treatment. Our findings suggest that prednisolone modulates the pro-inflammatory cytokines studied here either directly or through suppression of the immune cells producing these inflammatory cytokines.

Clinico-pathological features of erythema nodosum leprosum: A case-control study at ALERT hospital, Ethiopia.

BACKGROUND: Leprosy reactions are a significant cause of morbidity in leprosy population. Erythema nodosum leprosum (ENL) is an immunological complication affecting approximately 50% of patients with lepromatous leprosy (LL) and 10% of borderline lepromatous (BL) leprosy. ENL is associated with clinical features such as skin lesions, neuritis, arthritis, dactylitis, eye inflammation, osteitis, orchitis, lymphadenitis and nephritis. ENL is treated mainly with corticosteroids and corticosteroids are often required for extended periods of time which may lead to serious adverse effects. High mortality rate and increased morbidity associated with corticosteroid treatment of ENL has been reported. For improved and evidence-based treatment of ENL, documenting the systems affected by ENL is important. We report here the clinical features of ENL in a cohort of patients with acute ENL who were recruited for a clinico-pathological study before and after prednisolone treatment. MATERIALS AND METHODS: A case-control study was performed at ALERT hospital, Ethiopia. Forty-six LL patients with ENL and 31 non-reactional LL matched controls were enrolled to the study and followed for 28 weeks. Clinical features were systematically documented at three visits (before, during and after predinsolone treatment of ENL cases) using a specifically designed form. Skin biopsy samples were obtained from each patient before and after treatment and used for histopathological investigations to supplement the clinical data. RESULTS: Pain was the most common symptom reported (98%) by patients with ENL. Eighty percent of them had reported skin pain and more than 70% had nerve and joint pain at enrolment. About 40% of the patients developed chronic ENL. Most individuals 95.7% had nodular skin lesions. Over half of patients with ENL had old nerve function impairment (NFI) while 13% had new NFI at enrolment. Facial and limb oedema were present in 60% patients. Regarding pathological findings before treatment, dermal neutrophilic infiltration was noted in 58.8% of patients with ENL compared to 14.3% in LL controls. Only 14.7% patients with ENL had evidence of vasculitis at enrolment. CONCLUSION: In our study, painful nodular skin lesions were present in all ENL patients. Only 58% patients had dermal polymorphonuclear cell infiltration showing that not all clinically confirmed ENL cases have neutrophilic infiltration in lesions. Very few patients had histological evidence of vasculitis. Many patients developed chronic ENL and these patients require inpatient corticosteroid treatment for extended periods which challenges the health service facility in resource poor settings, as well as the patient's quality of life.

A Systematic Review of Immunological Studies of Erythema Nodosum Leprosum.

Erythema nodosum leprosum (ENL) is a painful inflammatory complication of leprosy occurring in 50% of lepromatous leprosy patients and 5-10% of borderline lepromatous patients. It is a significant cause of economic hardship, morbidity and mortality in leprosy patients. Our understanding of the causes of ENL is limited. We performed a systematic review of the published literature and critically evaluated the evidence for the role of neutrophils, immune complexes (ICs), T-cells, cytokines, and other immunological factors that could contribute to the development of ENL. Searches of the literature were performed in PubMed. Studies, independent of published date, using samples from patients with ENL were included. The search revealed more than 20,000 articles of which 146 eligible studies were included in this systematic review. The studies demonstrate that ENL may be associated with a neutrophilic infiltrate, but it is not clear whether it is an IC-mediated process or that the presence of ICs is an epiphenomenon. Increased levels of tumor necrosis factor-α and other pro-inflammatory cytokines support the role of this cytokine in the inflammatory phase of ENL but not necessarily the initiation. T-cell subsets appear to be important in ENL since multiple studies report an increased CD4+/CD8+ ratio in both skin and peripheral blood of patients with ENL. Microarray data have identified new molecules and whole pathophysiological pathways associated with ENL and provides new insights into the pathogenesis of ENL. Studies of ENL are often difficult to compare due to a lack of case definitions, treatment status, and timing of sampling as well as the use of different laboratory techniques. A standardized approach to some of these issues would be useful. ENL appears to be a complex interaction of various aspects of the immune system. Rigorous clinical descriptions of well-defined cohorts of patients and a systems biology approach using available technologies such as genomics, epigenomics, transcriptomics, and proteomics could yield greater understanding of the condition.

Mycobacterium leprae Activates Toll-Like Receptor-4 Signaling and Expression on Macrophages Depending on Previous Bacillus Calmette-Guerin Vaccination.

Toll-like receptor (TLR)-1 and TLR2 have been shown to be receptors for Mycobacterium leprae (M. leprae), yet it is unclear whether M. leprae can signal through alternative TLRs. Other mycobacterial species possess ligands for TLR4 and genetic association studies in human populations suggest that people with TLR4 polymorphisms may be protected against leprosy. Using human embryonic kidney (HEK)-293 cells co-transfected with TLR4, we demonstrate that M. leprae activates TLR4. We used human macrophages to show that M. leprae stimulation of cytokine production is diminished if pre-treated with TLR4 neutralizing antibody. TLR4 protein expression was up-regulated on macrophages derived from non-bacillus Calmette-Guerin (BCG) vaccinated healthy volunteers after incubation with M. leprae, whereas it was down-regulated in macrophages derived from BCG-vaccinated donors. Finally, pre-treatment of macrophages derived from BCG-naive donors with BCG reversed the effect of M. leprae on TLR4 expression. This may be a newly described phenomenon by which BCG vaccination stimulates "non-specific" protection to the human immune system.

Human beta-defensin 3 is up-regulated in cutaneous leprosy type 1 reactions.

BACKGROUND: Leprosy, a chronic granulomatous disease affecting the skin and nerves, is caused by Mycobacterium leprae (M. leprae). The type of leprosy developed depends upon the host immune response. Type 1 reactions (T1Rs), that complicate borderline and lepromatous leprosy, are due to an increase in cell-mediated immunity and manifest as nerve damage and skin inflammation. Owing to the increase in inflammation in the skin of patients with T1Rs, we sought to investigate the activation of the innate immune system during reactionary events. Specifically, we investigated the expression levels of human beta-defensins (hBDs) 2 and 3 in the skin of patients with T1Rs, in keratinocytes, and in macrophages stimulated with M. leprae and corticosteroids. RESULTS: Skin biopsies from twenty-three patients with Type 1 reactions were found to have higher transcript levels of hBD3 as compared to fifteen leprosy patients without Type 1 reactions, as measured by qPCR. Moreover, we observed that keratinocytes but not macrophages up-regulated hBD2 and hBD3 in response to M. leprae stimulation in vitro. Corticosteroid treatment of patients with T1Rs caused a suppression of hBD2 and hBD3 in skin biopsies, as measured by qPCR. In vitro, corticosteroids suppressed M. leprae-dependent induction of hBD2 and hBD3 in keratinocytes. CONCLUSIONS: This study demonstrates that hBD3 is induced in leprosy Type 1 Reactions and suppressed by corticosteroids. Furthermore, our findings demonstrate that keratinocytes are responsive to M. leprae and lend support for additional studies on keratinocyte innate immunity in leprosy and T1Rs. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN31894035.

Leprosy type 1 reactions and erythema nodosum leprosum: [review]

Leprosy reactions are a major cause of nerve damage and morbidity in a significant proportion of leprosy patients. Reactions are immunologically mediated and can occur even after successful completion of multi-drug therapy. This review focuses on the epidemiology, pathology and treatment of leprosy type 1 reactions, erythema nodosum leprosum and silent neuropathy.

As reações hansênicas são a principal causa de dano e morbidade neural em grande parte dos pacientes hansênicos. São imunomediadas e podem ocorrer mesmo após o término bem sucedido da poliquimioterapia. Esta revisão enfoca a epidemiologia, a patologia e o tratamento das reações hansênicas do tipo 1, do eritema nodoso hansênico e da neuropatia silenciosa.

Leprosy.

Leprosy is a granulomatous disease affecting the skin and nerves caused by Mycobacterium leprae. It continues to be a significant public health problem. Despite multidrug therapy, immunologic reactions continue to occur, leading to disability and deformity due to neuropathy. It is important that dermatologists are aware of the neurologic as well as the skin manifestations of the condition so that nerve involvement can be identified and treated rapidly.