Marcelo Grossi Araújo

Epidemiology, Treatment, and Prevention of Human T-Cell Leukemia Virus Type 1-Associated Diseases

SUMMARY Human T-cell leukemia virus type 1 (HTLV-1), the first human retrovirus to be discovered, is present in diverse regions of the world, where its infection is usually neglected in health care settings and by public health authorities. Since it is usually asymptomatic in the beginning of the infection and disease typically manifests later in life, silent transmission occurs, which is associated with sexual relations, breastfeeding, and blood transfusions. There are no prospects of vaccines, and screening of blood banks and in prenatal care settings is not universal. Therefore, its transmission is active in many areas such as parts of Africa, South and Central America, the Caribbean region, Asia, and Melanesia. It causes serious diseases in humans, including adult T-cell leukemia/lymphoma (ATL) and an incapacitating neurological disease (HTLV-associated myelopathy/tropical spastic paraparesis [HAM/TSP]) besides other afflictions such as uveitis, rheumatic syndromes, and predisposition to helminthic and bacterial infections, among others. These diseases are not curable as yet, and current treatments as well as new perspectives are discussed in the present review.

Leprosy in Brazil

Leprosy or Hansens disease is a chronic infectious disease caused by the Mycobacterium leprae. The skin and nervous manifestations of the disease present a singular clinical picture that is easily recognized. After India, Brazil still is the second country with the greatest number of cases in the world. Around 94% of the known cases and 94% of the new cases reported in America, come from Brazil. The disease presents itself in two well-defined stable and opposite poles (lepromatous and tuberculoid) and two unstable groups (indeterminate and dimorphic). The spectrum of presentation of the disease may also be classified as: tuberculoid tuberculoid (TT), borderline tuberculoid (BT), borderline borderline (BB), borderline lepromatous (BL) and lepromatous lepromatous (LL). The finding of acid fast bacillus in tissue is the most useful method of diagnosis. The effective treatment of leprosy includes the use of specific therapy, suppression of lepra reactions, prevention of physical incapacity, and physical and psychosocial rehabilitation. Chemotherapy with rifampin, dapsone and clofazimine have produced very good results and the control of the disease in Brazil in the foreseeable future is likely.

Immunological profile of HTLV-1-infected patients associated with infectious or autoimmune dermatological disorders.

In the present study, the frequency, the activation and the cytokine and chemokine profile of HTLV-1 carriers with or without dermatological lesions were thoroughly described and compared. The results indicated that HTLV-1-infected patients with dermatological lesions have distinct frequency and activation status when compared to asymptomatic carriers. Alterations in the CD4+HLA-DR+, CD8+ T cell, macrophage-like and NKT subsets as well as in the serum chemokines CCL5, CXCL8, CXCL9 and CXCL10 were observed in the HTLV-1-infected group with skin lesions. Additionally, HTLV-1 carriers with dermatological skin lesions showed more frequently high proviral load as compared to asymptomatic carriers. The elevated proviral load in HTLV-1 patients with infectious skin lesions correlated significantly with TNF-α/IL-10 ratio, while the same significant correlation was found for the IL-12/IL-10 ratio and the high proviral load in HTLV-1-infected patients with autoimmune skin lesions. All in all, these results suggest a distinct and unique immunological profile in the peripheral blood of HTLV-1-infected patients with skin disorders, and the different nature of skin lesion observed in these patients may be an outcome of a distinct unbalance of the systemic inflammatory response upon HTLV-1 infection.

Characterization of MicroRNA Expression Profiles and Identification of Potential Biomarkers in Leprosy

ABSTRACT Leprosy is an important cause of disability in the developing world. Early diagnosis is essential to allow for cure and to interrupt transmission of this infection. MicroRNAs (miRNAs) are important factors for host-pathogen interaction and they have been identified as biomarkers for various infectious diseases. The expression profile of 377 microRNAs were analyzed by TaqMan low-density array (TLDA) in skin lesions of tuberculoid and lepromatous leprosy patients as well as skin specimens from healthy controls. In a second step, 16 microRNAs were selected for validation experiments with reverse transcription-quantitative PCR (qRT-PCR) in skin samples from new individuals. Principal-component analysis followed by logistic regression model and receiver operating characteristic (ROC) curve analyses were performed to evaluate the diagnostic potential of selected miRNAs. Four patterns of differential expression were identified in the TLDA experiment, suggesting a diagnostic potential of miRNAs in leprosy. After validation experiments, a combination of four miRNAs (miR-101, miR-196b, miR-27b, and miR-29c) was revealed as able to discriminate between healthy control and leprosy patients with 80% sensitivity and 91% specificity. This set of miRNAs was also able to discriminate between lepromatous and tuberculoid patients with a sensitivity of 83% and 80% specificity. In this work, it was possible to identify a set of miRNAs with good diagnostic potential for leprosy.

Uniform multidrug therapy for leprosy patients in Brazil (U-MDT/CT-BR): Results of an open label, randomized and controlled clinical trial, among multibacillary patients

Background Leprosy control is based on early diagnosis and multidrug therapy. For treatment purposes, leprosy patients can be classified as paucibacillary (PB) or multibacillary (MB), according to the number of skin lesions. Studies regarding a uniform treatment regimen (U-MDT) for all leprosy patients have been encouraged by the WHO, rendering disease classification unnecessary. Methodology and findings An independent, randomized, controlled clinical trial conducted from 2007 to 2015 in Brazil, compared main outcomes (frequency of reactions, bacilloscopic index trend, disability progression and relapse rates) among MB patients treated with a uniform regimen/U-MDT (dapsone+rifampicin+clofazimine for six months) versus WHO regular-MDT/R-MDT (dapsone+rifampicin+clofazimine for 12 months). A total of 613 newly diagnosed, untreated MB patients with high bacterial load were included. There was no statistically significant difference in Kaplan-Meyer survival function regarding reaction or disability progression among patients in the U-MDT and R-MDT groups, with more than 25% disability progression in both groups. The full mixed effects model adjusted for the bacilloscopic index average trend in time showed no statistically significant difference for the regression coefficient in both groups and for interaction variables that included treatment group. During active follow up, four patients in U-MDT group relapsed representing a relapse rate of 2.6 per 1000 patients per year of active follow up (95% CI [0·81, 6·2] per 1000). During passive follow up three patients relapsed in U-MDT and one in R-MTD. As this period corresponds to passive follow up, sensitivity analysis estimated the relapse rate for the entire follow up period between 2·9- and 4·5 per 1000 people per year. Conclusion Our results on the first randomized and controlled study on U-MDT together with the results from three previous studies performed in China, India and Bangladesh, support the hypothesis that UMDT is an acceptable option to be adopted in endemic countries to treat leprosy patients in the field worldwide. Trial registration ClinicalTrials.gov: NCT00669643

Teaching of leprosy: current challenges

In the context of declining leprosy endemicity worldwide, keeping the interest in knowledge and expertise in leprosy alive has been a matter of concern. Approaching the problem only in primary care, without the proper integration with other levels of care in the health system fails to account for the complexity of the disease. Training professionals to work at different levels of health care is a current challenge. The objective of this review was to look for experiences related to the teaching of leprosy both in undergraduate courses in the field of health sciences and in training programs for professionals who work in patient care. We highlight the role of the dermatologist in the management of control programs, diagnosis and treatment of the disease, as well as in the continuous education of other health professionals.

Hanseníase multibacilar em paciente transplantado renal: relato de caso

Leprosy is still a public health concern in Brazil, where more than 30,000 new cases are detected every year. There are few reports of this mycobacteriosis in immunosuppressed patients, despite the increasing number of solid organ transplantation and the use of post-transplant drugs in this country. The authors describe a case of multibacillary leprosy in a renal transplant recipient, detected 12 years after the procedure, and discuss the therapy, adverse effects and management of leprosy reactions in patients immunosuppressed by drugs.

Manifestações cutâneas da infecção e das doenças relacionadas ao vírus linfotrópico de células T humanas do tipo 1

Humam T lymphotropic virus type 1 (HTLV-1) has heteregenous distribution world-wide and, in Brazil, there are high prevalence areas. HTLV-1 has been associated to severe diseases, such as adult T cell leukaemia/ lymphoma, HTLV-1 associated myelopahthy/ tropical spastic parapesis, HTLV-1 associated uveitis and HTLV-1 associated infective dermatitis. Genetics, proviral load and infection route are related to disease risk along life. The lifetime risk to develop HTLV-1 related diseases may be close to 10%. Skin lesions are known to occur in the course of HTLV-1 related diseases and also in asymptomatic carries. Xerosis, dermatophytosis and recurrent infections are among the most common found skin diseases. In this paper the authors reviewed the major associated diseases and aspects of the HTLV-1 infection itself, with emphasis on skin manifestation in the context.

Phenotypic and functional features of innate and adaptive immunity as putative biomarkers for clinical status and leprosy reactions

The aim of this study was to identify phenotypic and functional biomarkers associated with distinct clinical status of leprosy or leprosy reactions. The study included tuberculoid/borderline (BB/BT/T) and lepromatous (BL/L) leprosy poles as well as Type-1 and Type-2 leprosy reactions along with healthy controls (NI). A range of peripheral blood biomarkers of innate (neutrophils - NEU and monocytes - MON) and adaptive immunity (CD4+ and CD8+ T-cells) were evaluated ex vivo and upon in vitro stimuli with M. leprae antigen. Data analysis allowed the selection of NEUTLR4+ (ex vivo) and CD4+IL-10+ (in vitro) as universal biomarkers increased in all leprosy patients and those exhibiting leprosy reactions. A range of biomarkers were commonly found in both poles of leprosy patients, including decreased levels of MONTGF-β+ (ex vivo) and increased levels of MONTNF-α+, CD4+TGF-β+, CD8+TLR2+, CD8+TNF-α+, CD8+IL-4+ and CD8+TGF-β+ (in vitro). Noteworthy was that MONHLA-DR+ (ex vivo) and CD8+IL-10+ (in vitro) were particularly found in BL/L patients. Leprosy patients with Type-1 reaction exhibited a larger list of altered biomarkers, mainly involving activation markers (TLR2, TLR4, HLA-DR and DAF-2T) in NEU and MON along with CD4+ and CD8+ cells. In summary, this study provided insights about immunological features of leprosy poles and leprosy reactional episodes with putative applicability, including novel biomarkers for complementary diagnosis and future therapeutic approaches in clinical studies.

Tacrolimus-induced symmetric drug-related intertriginous and flexural exanthema (SDRIFE): TACROLIMUS-INDUCED SDRIFE

Conflict of interests: None declared. use, and very few following systemic administration (1, 2). Symmetric drug-related intertriginous and flexural exanthema (SDRIFE) results from systemic drug exposure. The diagnosis is established if four of the following five criteria are met: exposure to a systemic drug; erythema of the gluteal, inguinal or axillary area; involvement of at least one intertriginous site; symmetry; and the absence of systemic toxicity (2, 3).