Resumo em Inglês:

Abstract Leprosy remains a public health problem in developing countries. Among communicable diseases, it is one of the leading causes of permanent disability. Brazil had not reached the goal of reducing cases to less than 1 per 10,000 population. This study aimed to analyze the spatial distribution of leprosy cases in Brazil, using a literature review. The search strategy included the LILACS and MEDLINE databases with no language or period restriction. Ecological studies with spatial data analysis were considered as a criterion for the inclusion. We found 38 studies for review after the selection criteria. Among the epidemiological indicators of the disease, the most common was the new case detection rate. Several articles have explored the association between spatial distribution of leprosy and socioeconomic, demographic, and environmental factors. The most common unit of analysis was the municipality. The spatial distribution methods mostly used were: empirical Bayesian method, autocorrelation (Moran’s I index) and Kernel estimates. The distribution of leprosy was very heterogeneous, independent of the unit of analysis. There was a decrease in the rate of detection and among under-15-year-olds, but some regions maintained high endemicity during the study period. The distribution and risk of illness were directly related to living conditions of the population. Improved access to health services was associated with increased detection rate in some regions. Spatial analysis seems to be a very useful tool to study leprosy and to guide interventions and surveillance.

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Abstract The Zika virus (ZIKV) epidemic has become a public health emergency following its association with severe neurological complications. We aim to discuss how the Brazilian National Health Information Systems can help to assess the impact of the ZIKV epidemic on health outcomes potentially related to ZIKV. Health outcomes potentially related to ZIKV infection were described based on a literature review of published studies on ZIKV infection outcomes and on recent protocols developed and published by the Brazilian Ministry of Health for different stages of the life cycle. These outcomes were correlated with the International Classification of Diseases 10th Revision (ICD-10) classification system, as this is the diagnostic classification registered in the Health Information System. A suggested list of 50 clinical manifestations, dispersed into 4 ICD chapters, and their information sources was created to help monitor the ZIKV epidemics and trends. Correlation of these selected ICD-10 codes and the HIS, as well as, a review of the potentialities and limitations of health information systems were performed. The potential of the Health Information System and its underutilization by stakeholders and researchers have been a barrier in diagnosing and reporting ZIKV infection and its complications. The ZIKV outbreak is still a challenge for health practice and the Brazilian Health Information System.

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Abstract Human brucellosis is a re-emerging disease with the potential for bioterrorism. The number of cases in Brazil has increased; however, the ideal management has not been established. These guidelines are intended for use by clinicians and other health-care workers providing medical care for patients with suspected brucellosis in the State of Paraná. We included a brief description of the epidemiology, clinical presentation, diagnosis, prevention of exposure, prevention of disease by chemoprophylaxis, treatment of disease, monitoring of adverse effects during treatment, management of treatment failure and relapse cases.

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Abstract INTRODUCTION: Chikungunya fever is a condition resulting from infection by chikungunya virus (CHIKV), an Aedes sp.-transmitted virus. This disease has been diagnosed in thousands of cases in the Americas, particularly in Brazil, in recent years, and there is an ongoing epidemic of chikungunya fever in Brazil that began in 2014. Clinical diagnosis is difficult; only a few cases have been confirmed by laboratory tests due to the low number of specific, efficient tests available for virus or antibody detection. Here, we aimed to evaluate different polymerase chain reaction (PCR) approaches for detection of CHIKV genetic material. METHODS: Specific primers and probes within the viral capsid gene region were designed for this work. To evaluate the analytic sensitivity of detection, human sera were spiked with serial dilutions of the viral stock. Several PCR protocols were performed to investigate the sensitivity of CHIKV RNA detection in serum dilutions ranging from 106 to 1 PFU equivalents. RESULTS: The technique showing the greatest sensitivity was a real-time PCR assay using specific probes that could detect the genetic material of the virus at all dilutions, followed by conventional PCR. Digital PCR showed low sensitivity and was much more expensive than other technologies. Digital PCR should be used for specific purposes other than clinical diagnosis. CONCLUSIONS: Although quantitative PCR using probes was more expensive than the use of intercalating dyes or conventional PCR, it had the highest sensitivity out of all tested PCR approaches.

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Abstract INTRODUCTION: HIV and viral hepatitis infections are major causes of chronic disease worldwide and have some similarities with regard to routes of transmission, epidemiology, front barriers faced during access of treatment, and strategies for a global public health response. The objective was to describe the HIV-1 subtypes, viral tropism and single-nucleotide polymorphisms (SNPs) of interleukin 28B (IL28B) from a case series of HIV/viral hepatitis coinfected patients from southern Brazil. METHODS: Clinical and epidemiological data were evaluated by a review of medical records. Periodic blood draws were taken to determine the viral and host characteristics. RESULTS: This study included 38 patients with HIV/HBV or HIV/HCV coinfection; the median age was 49 years. Thirty-seven (97.4%) were on antiretroviral therapy, 32 (84.2%) had an undetectable viral load, a median CD4+ T-cell count of 452 cells/mm3. HIV-1 subtyping showed 47.4 and 31.6% of patients with subtypes C and B, respectively. Analysis of viral co-receptor usage showed a predominance of the R5 variant (64.7%), with no significant difference between the subtypes. Twenty patients with HIV/HCV coinfection were eligible to receive HCV therapy with pegylated-interferon-alpha plus ribavirin, and 10/20 (50%) of them achieved sustained virological response. SNPs of IL28B were evaluated in 93.3% of patients with HIV/HCV coinfection, and 17 (60.7%) presented the CC genotype. CONCLUSIONS: In the present case series, a higher frequency of HIV subtype C was found in coinfected patients. However such findings need to be prospectively evaluated with the inclusion of data from regional multicenter analyses.

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Abstract INTRODUCTION: The drugs available for visceral leishmaniasis (VL) treatment in Brazil have specific characteristics in terms of operability, effectiveness, toxicity, and cost. The aim of this study was to estimate the direct costs of therapies recommended by the Ministry of Health (MH) for VL treatment in Brazil. METHODS: The analytical perspective used was that adopted by the Brazilian Public Health System. Three drugs and four regimens were included: 1) N-methyl glucamine antimoniate intramuscularly at 20mg per kg per day for 30 days; 2) N-methyl glucamine antimoniate intravenously at 20mg per kg per day for 30 days; 3) amphotericin B deoxycholate at 1mg per kg per day for 21 days; and 4) liposomal amphotericin B at 3mg per kg per day for a 7 days treatment. RESULTS: The estimated direct costs of treatment for an adult patient using N-methylglucamine antimoniate administered via the intramuscular and intravenous routes were USD 418.52 and USD 669.40, respectively. The estimated cost of treatment with amphotericin B deoxycholate was USD 1,522.70. Finally, the estimated costs of treatment with liposomal amphotericin B were USD 659.79, and USD 11,559.15 using the price adopted by the WHO and the Drug Regulation Board, respectively. CONCLUSIONS: This analysis indicates the economic feasibility of replacing N-methyl glucamine antimoniate with liposomal amphotericin B, which allows a shorter treatment period with less toxicity compared with other treatments, provided that the purchase value used by the WHO and transferred to the MH is maintained.

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Abstract INTRODUCTION The control of reservoirs for Leishmania infantum -induced zoonotic visceral leishmaniasis requires the identification of dogs posing a population risk. Here, we assessed the performance of several assays to identify Lutzomyia longipalpis infectious dogs. METHODS We evaluated 99 dogs that were positive for visceral leishmaniasis based on parasite identification. Serological analyses were performed using an enzyme-linked immunosorbent assay, immunofluorescence antibody tests in 1:40 and 1:80 dilutions, rapid dual path platform tests, immunochromatographic assay with a recombinant rK39 antigen, fast agglutination screening tests, and direct agglutination tests. We also performed PCR to analyze peripheral blood and xenodiagnosis. RESULTS Forty-six dogs infected at least one L. longipalpis specimen. Although the serological test sensitivities were above 85% for detecting L. longipalpis infectious dogs, none showed a satisfactory performance, as both specificity (0.06 to 13%) and the area under the receiver operating characteristic curve (45 to 53%) were low. The PCR results were also weak, with a sensitivity of 30%, specificity of 72%, and an area under the receiver operating characteristic curve of 51%. The infected L. longipalpis proportion was higher among asymptomatic dogs than symptomatic dogs. Among the symptomatic dogs, those with ulceration-free skin diseases were more infectious, with an odds ratio of 9.3 (confidence interval of 1.10 - 428.5). The larger the number of insects fed, the greater the detected infectiousness. CONCLUSIONS Our study supports the imperative to develop novel technologies for identifying the infectious dogs that transmit L. infantum for the benefit of public health.

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Abstract INTRODUCTION Renal damage is a consequence of severe malaria, and is generally caused by sequestration of Plasmodium falciparum -infected erythrocytes in the renal microcirculation, which leads to obstruction, hypoxia, and ischemia. This triggers high mobility group box 1 (HMGB1) to send a danger signal through toll-like receptors 2 and 4. This signal up-regulates inducible nitric oxide (iNOS) and nitrotyrosine to re-perfuse the tissue, and also increases heat shock protein 70 (HSP70) expression. As no study has examined the involvement of intracellular secondary molecules in this setting, the present study compared the renal expressions of HSP70, HMGB1, iNOS, and nitrotyrosine between mice suffered from severe malaria and normal mice. METHODS C57BL/6 mice were divided into an infected group (intraperitoneal injection of 10 6 P. berghei ANKA) and a non-infected group. Renal damage was evaluated using hematoxylin eosin staining, and immunohistochemistry was used to evaluate the expressions of HSP70, HMGB1, iNOS, and nitrotyrosine. RESULTS Significant inter-group differences were observed in the renal expressions of HSP70, HMGB1, and iNOS (p=0.000, Mann-Whitney test), as well as nitrotyrosine (p=0.000, independent t test). The expressions of HSP70 and HMGB1 were strongly correlated (p=0.000, R=1.000). No correlations were observed between iNOS and HMGB, HMGB1 and nitrotyrosine, HSP70 and nitrotyrosine, or iNOS and nitrotyrosine. CONCLUSIONS It appears that HMGB1, HSP70, iNOS, and nitrotyrosine play roles in the renal damage that is observed in mice with severe malaria. Only HSP70 expression is strongly correlated with the expression of HMGB1.

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Abstract INTRODUCTION: Primaquine (PQ) diphosphate is an 8-aminoquinoline antimalarial drug with unique therapeutic properties. It is the only drug that prevents relapses of Plasmodium vivax or Plasmodium ovale infections. In this study, a fast, sensitive, cost-effective, and robust method for the extraction and high-performance liquid chromatography with diode array ultraviolet detection (HPLC-DAD-UV ) analysis of PQ in the blood plasma was developed and validated. METHODS: After plasma protein precipitation, PQ was obtained by liquid-liquid extraction and analyzed by HPLC-DAD-UV with a modified-silica cyanopropyl column (250mm × 4.6mm i.d. × 5μm) as the stationary phase and a mixture of acetonitrile and 10mM ammonium acetate buffer (pH = 3.80) (45:55) as the mobile phase. The flow rate was 1.0mL·min-1, the oven temperature was 50OC, and absorbance was measured at 264nm. The method was validated for linearity, intra-day and inter-day precision, accuracy, recovery, and robustness. The detection (LOD) and quantification (LOQ) limits were 1.0 and 3.5ng·mL-1, respectively. The method was used to analyze the plasma of female DBA-2 mice treated with 20mg.kg-1 (oral) PQ diphosphate. RESULTS: By combining a simple, low-cost extraction procedure with a sensitive, precise, accurate, and robust method, it was possible to analyze PQ in small volumes of plasma. The new method presents lower LOD and LOQ limits and requires a shorter analysis time and smaller plasma volumes than those of previously reported HPLC methods with DAD-UV detection. CONCLUSIONS: The new validated method is suitable for kinetic studies of PQ in small rodents, including mouse models for the study of malaria.

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Abstract INTRODUCTION In order to detect Trypanosoma cruzi and determine the genetic profiles of the parasite during the chronic phase of Chagas disease (ChD), parasitological and molecular diagnostic methods were used to assess the blood of 91 patients without specific prior treatment. METHODS Blood samples were collected from 68 patients with cardiac ChD and 23 patients with an indeterminate form of ChD, followed by evaluation using blood culture and polymerase chain reaction. T . cruzi isolates were genotyped using three different genetic markers. RESULTS: Blood culture was positive in 54.9% of all patients, among which 60.3% had the cardiac form of ChD, and 39.1% the indeterminate form of ChD. There were no significant differences in blood culture positivity among patients with cardiac and indeterminate forms. Additionally, patient age and clinical forms did not influence blood culture results. Polymerase chain reaction (PCR) was positive in 98.9% of patients, although comparisons between blood culture and PCR results showed that the two techniques did not agree. Forty-two T . cruzi stocks were isolated, and TcII was detected in 95.2% of isolates. Additionally, one isolate corresponded to TcIII or TcIV, and another corresponded to TcV or TcVI. CONCLUSIONS Blood culture and PCR were both effective for identifying T. cruzi using a single blood sample, and their association did not improve parasite detection. However, we were not able to establish an association between the clinical form of ChD and the genetic profile of the parasite.

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Abstract INTRODUCTION: Trypanosoma cruzi (Tc) infection is usually acquired in childhood in endemic areas, leading to Chagas disease, which progresses to Chagas cardiomyopathy in 20-30% of infected individuals over decades. The pathogenesis of Chagas cardiomyopathy involves the host inflammatory response to T. cruzi, in which upstream caspase-1 activation prompts the cascade of inflammatory chemokines/cytokines, cardiac remodeling, and myocardial dysfunction. The aim of the present study was to examine the association of two caspase-1 single nucleotide polymorphisms (SNPs) with cardiomyopathy. METHODS: We recruited infected (Tc+, n = 149) and uninfected (Tc−, n = 87) participants in a hospital in Santa Cruz, Bolivia. Cardiac status was classified (I, II, III, IV) based on Chagas cardiomyopathy-associated electrocardiogram findings and ejection fractions on echocardiogram. Genotypes were determined using Taqman probes via reverse transcription-polymerase chain reaction of peripheral blood DNA. Genotype frequencies were analyzed according to three inheritance patterns (dominant, recessive, additive) using logistic regression adjusted for age and sex. RESULTS: The AA allele for the caspase-1 SNP rs501192 was more frequent in Tc+ cardiomyopathy (classes II, III, IV) patients compared to those with a normal cardiac status (class I) [odds ratio (OR) = −2.18, p = 0.117]. This trend approached statistical significant considering only Tc+ patients in class I and II (OR = −2.64, p = 0.064). CONCLUSIONS: Caspase-1 polymorphisms may play a role in Chagas cardiomyopathy development and could serve as markers to identify individuals at higher risk for priority treatment.

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Abstract INTRODUCTION Citronellal (Cit) possesses antifungal activity and has possible implications for reactive oxygen species (ROS) generation in Candida albicans. In this study, the effects of Cit on ROS generation and the mechanisms by which Cit exerts anti-Candida effects were examined. METHODS A 2′,7′-dichlorodihydrofluorescein diacetate assay was used to assess oxidative damage. Cell necrosis was determined by flow cytometry after FITC-Annexin V staining. Mitochondrial function was studied based on mitochondrial potential, metabolic activity (MTT assay), and phenotypic susceptibility on a non-fermentable carbon source. Membrane intactness and DNA damage were estimated by a propidium iodide (PI) uptake assay and 4',6-diamidino-2-phenylindole (DAPI) staining. RESULTS ROS generation was enhanced in response to Cit, leading to necrosis (2%). Additional hallmarks of cell death in response to Cit, such as mitochondrial membrane depolarization and DNA damage, were also observed. Cit treatment resulted in dysfunctional mitochondria, as evidenced by poor labeling with the mitochondrial membrane potential-sensitive probe rhodamine B, reduced metabolic activity (61.5%), and inhibited growth on a non-fermentable carbon source. Furthermore, Cit induced DNA damage based on DAPI staining. These phenotypes were reinforced by RT-PCR showing differences in gene expression (30-60%) between control and Cit-treated cells. Finally, PI uptake in the presence of sodium azide confirmed non-intact membranes and suggested that Cit activity is independent of the energy status of the cell. CONCLUSIONS Cit possesses dual anticandidal mechanisms, including membrane-disruptive and oxidative damage. Taken together, our data demonstrated that cit could be used as a prominent antifungal drug.

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Abstract INTRODUCTION: Emerging diseases are of great interest, especially those associated with high mortality rates such as hantaviruses. We aimed to conduct a seroepidemiological survey to determine the levels of hantavirus infection. METHODS: In-house enzyme-linked immunosorbent assay (ELISA) was used to detect specific antibodies. RESULTS: Of the 429 samples collected, seropositivity of 3.9% to anti-hantavirus immunoglobulin G (IgG) was observed (CI 95%: 2.3-5.7). Moreover, in three cases, immunoglobulin M (IgM) was detected, of which two were diagnosed as hantavirus cardiopulmonary syndrome (HCPS). CONCLUSIONS: Our data indicate the considerable occurrence of previous hantavirus infections, highlighting occurrences from sub-clinical cases to HCPS.

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Abstract INTRODUCTION: Neglected infectious diseases like mumps may be opportunistic in controlled areas with low vaccine coverage, particularly in developed and emerging countries. METHODS: A retrospective analysis of mumps-related data from 2001 to 2016 for São Paulo State, Brazil was conducted. RESULTS: From 2014 to 2015, there was an increase of 82% in reported mumps cases in São Paulo, with prevalence of n=49 and 297, respectively in young adults aged 15-29 years. CONCLUSIONS: A booster-shot campaign on MMR vaccination is recommended to prevent the spread of mumps in unvaccinated children and recipients of only the first dose.

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Abstract INTRODUCTION: Cacipacore virus (CPCV), a possible bird-associated flavivirus, has yet to be detected in mosquitoes. Our purpose is examining CPCV in mosquitoes from the Amazon region of Brazil. METHODS: Approximately 3,253 Culicidae (grouped into 264 pools) were collected from the Amazon region during 2002-2006 and analyzed using a Flavivirus genus-specific reverse transcription- polymerase chain reaction followed by nested polymerase chain reaction assay and by nucleotide sequencing of amplicons. RESULTS: Nucleotide sequences from five mosquito samples showed high similarity to the those of CPCV originally isolated in the Amazon region. CONCLUSIONS: This is the first report of CPCV-infected mosquitoes which has implications on the arbovirus maintenance in nature and transmission to man.

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Abstract INTRODUCTION: Studying the feeding preferences of triatomines is an important entomological surveillance tool, since continuous surveillance of the disease is necessary. METHODS: The precipitin reaction was used to describe the feeding preferences of triatomines along with their natural infection by flagellates similar to Tyrpanosoma cruzi. Six hundred eighty-seven insects were examined, including Triatoma brasiliensis, Triatoma pseudomaculata, and Panstrongylus lutzi. RESULTS: Sixty-nine (10%) of 687 triatomines examined tested positive for flagellates similar to T. cruzi, and 8 (1.2%) of these fed on human blood. CONCLUSIONS: This study found potential transmitters of Chagas disease both inside and outside the domiciliar environment.

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Abstract INTRODUCTION: This study reports, for the first time, the presence of Panstrongylus lignarius in the State of Rondonia, Brazil. METHODS: Specimen of P. lignarius was collected from a flat in an urban area of the municipality of Porto Velho, Western Amazon. RESULTS: With this finding of P. lignarius, the number of Triatominae species in the State of Rondonia has increased from six to seven. CONCLUSIONS: The occurrence of P. lignarius is worrisome, because this species has been found to be naturally infected with Trypanosoma cruzi and there has been evidence of its domiciliation capabilities in other countries of South America.

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Abstract INTRODUCTION: This study aimed to evaluate a new commercial kit, Kit SIRE Nitratase-PlastLabor, for testing the drug susceptibility of clinical Mycobacterium tuberculosis isolates. METHODS: The accuracy of the Kit SIRE Nitratase was evaluated by examining the susceptibility (streptomycin, isoniazid, rifampicin, and ethambutol) of 40 M. tuberculosis isolates, using the proportion method with Lowenstein-Jensen medium or the BACTEC MGIT 960 system. RESULTS: The detection accuracy for streptomycin, isoniazid, rifampicin, and ethambutol was 95%, 97.5%, 100%, and 80%, respectively. CONCLUSIONS: The exceptional accuracy demonstrated by Kit SIRE Nitratase for isoniazid and rifampicin makes the kit an attractive option for screening M. tuberculosis strain resistance.

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Abstract INTRODUCTION: We compared indicators of oxidative stress in the tissue of mice infected with strains from Sporothrix schenckii complex. METHODS: Mice were inoculated with Sporothrix brasiliensis, Sporothrix schenckii sensu stricto, Sporothrix globosa, Sporothrix mexicana or Sporothrix albicans. The activity of catalase and glutathione were accessed in the liver and spleen. RESULTS: Animals infected with S. brasiliensis exhibited splenomegaly and significant decrease in catalase activity, and protein and non-protein thiol content compared to animals infected with the other species. CONCLUSIONS: Sporothrix brasiliensis exhibits higher pathogenicity compared to other species of the Sporothrix schenckii complex by increasing oxidative stress in animal tissue.

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Abstract INTRODUCTION: Candidaparapsilosis complex species, frequently found in hospital environments, have gained importance as etiological agents of candidemia. METHODS: Candidaparapsilosis complex isolates from a nosocomial environment were identified and their hydrolitic enzyme activity and ability to form biofilm were characterized. RESULTS: Twenty-two C. parapsilosis sensu stricto isolates produced proteinase and three produced phospholipase. Most Candida metapsilosis isolates produced proteinase and one also produced phospholipase. All 29 isolates formed biofilms. CONCLUSIONS: The nosocomial environment may act as a reservoir for C. parapsilosis complex isolates with phenotypic features that could possibly lead to nosocomial infections and health complications in hospital patients.

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Abstract Wade’s histoid leprosy (HL) is a rare variant of multibacillary leprosy, with characteristic clinical, immunologic, histopathologic, and bacteriologic features. It is associated with resistance to sulfa drugs or polychemotherapy and is rarely observed in patients who have not undergone prior treatment. Clinically, HL resembles keloid or dermatofibroma. Furthermore, HL is rare in children and is difficult to diagnose even by experts. This report describes a case of HL in a 14-year-old Brazilian boy, who presented with multiple nodular and tumor-like lesions, simulating keloids. He had not undergone prior treatment with anti-leprosy drugs, which accentuates the relevance of this case report.

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Abstract Seven months after undergoing kidney transplantation, a 56-year-old woman presented with papules and ulcers in her right forearm. The patient received antibiotics for 8 months with limited improvement. Eleven months after symptom onset, she presented with acute arthritis in her left knee. Asynovial fluid culture yielded Mycobacterium tuberculosis, and a forearm ulcer biopsy showed granulomatous inflammation. After surgical fistulectomy and 12 months of tuberculosis treatment, she was cured. Chronic cutaneous ulcers and articular manifestations in TB are rare, but they should always be considered in the differential diagnosis for immunosuppressed patients. Surgical intervention and prolonged treatment might be necessary.

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Abstract Myeloperoxidase (MOP) is present in monocyte and neutrophil lysosomes, catalyzing hydrogen peroxide and chloride ion conversion to hypochlorous acid. MOP seems to destroy pathogens during phagocytosis by neutrophils and is considered an important defense against innumerous bacteria. We present a patient who had MOP deficiency, who presented with a subacute form of paracoccidioidomycosis and later with peritoneal tuberculosis. MOP deficiency leads to the diminished destruction of phagocytized pathogens. This case gives important evidence of an association between MOP deficiency and increased susceptibility to infection by Paracoccidioides brasiliensis and Mycobacterium tuberculosis.

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Abstract Fascioliasis is a zoonotic disease caused by a leaf-like worm (fluke) called Fasciola. Herein, we present a case of human hepatic fascioliasis. A 57-year-old man was referred to the hospital for ambiguous gastrointestinal symptoms with suspected hemangioma. Hepatic fascioliasis was diagnosed using abdominal computed tomography and serology. He tested positive for the IgG antibody against Fasciola hepatica. The patient was treated successfully with triclabendazole. This is the first published report on the occurrence of fascioliasis in Northeast Iran, a non-endemic area for fascioliasis. Our results suggest the emergence of a new focus in the region.