André Ricardo Ribas Freitas

Specific Biomarkers Associated With Neurological Complications and Congenital Central Nervous System Abnormalities From Zika Virus–Infected Patients in Brazil

Summary The first systematic large-scale analysis of immune mediators reported in patients with Zika virus (ZIKV) infection. Several key immune mediators have been identified for the control of ZIKV pathogenesis. This will clarify the molecular mechanisms of ZIKV infection in patients.

Prevalence, Risk Factors and Molecular Characteristics of Meningococcal Carriage Among Brazilian Adolescents.

Background: In 2010, introduction of the meningococcal C conjugate vaccine in Brazil for children <2 years provided an immediate reduction in the incidence rates of disease among the age groups targeted for the vaccine, but no early impact was observed in unvaccinated age groups. Knowledge about meningococcal carriage is crucial for improving our understanding of the disease epidemiology and for designing effective vaccination programs. Taking in account the very limited published data currently available describing meningococcal carriage in Brazil, we performed a study to evaluate the prevalence of Neisseria meningitidis carriage among adolescent students. Methods: A cross-sectional study was conducted in 2012 to assess the prevalence of meningococcal carriage among a representative sample of 1208 students 11–19 years of age in Campinas, Brazil. Genotypic and phenotypic characterization of isolated carriage strains and the effect of potential risk factors for carriage were also analyzed. Results: The overall carriage prevalence was 9.9% (95% confidence interval, 8.3–11.8%), with dominance of serogroup C (1.32%), followed by serogroups B (0.99%), E (0.74%), Y (0.49%) and W (0.25%). A lower level of education of the parents was independently associated with a higher risk of carriage. A high diversity of genotypes was found among carriage strains. Conclusions: The evidence gathered during this study provides estimates of carriage prevalence in Brazilian adolescents, showing an unusually high dominance of serogroup C. These results have important implications in future strategies to optimize the impact of the current meningococcal C vaccination program in Brazil.

Surveillance of deaths caused by arboviruses in Brazil: from dengue to chikungunya

Did death occur DUE TO dengue, or in a patient WITH dengue virus infection? It seems a matter of semantics, but in fact, it underscores how challenging it is to distinguish whether the disease contributed to death, or was itself the underlying cause of death. Can a death be attributed to chikungunya virus, when some deaths occur after the acute phase? Did the virus decompensate the underlying diseases, leading to death? Did prolonged hospitalisation lead to infection, resulting in the patient’s progression to death? Were there iatrogenic complications during patient care? The dengue question, for which there has not yet been a definitive response, resurfaces prominently under the chikungunya surveillance scenario. We are facing an epidemic of a disease that seems to be more lethal than previously thought. The major challenge ahead is to investigate deaths suspected of occurring due to arbovirus infections and to understand the role of each infection in the unfavourable outcome.

Serum Metabolic Alterations upon Zika Infection

Zika virus (ZIKV) infection has recently emerged as a major concern worldwide due to its strong association with nervous system malformation (microcephaly) of fetuses in pregnant women infected by the virus. Signs and symptoms of ZIKV infection are often mistaken with other common viral infections. Since transmission may occur through biological fluids exchange and coitus, in addition to mosquito bite, this condition is an important infectious disease. Thus, understanding the mechanism of viral infection has become an important research focus, as well as providing potential targets for assertive clinical diagnosis and quality screening for hemoderivatives. Within this context, the present work analyzed blood plasma from 79 subjects, divided as a control group and a ZIKV-infected group. Samples underwent direct-infusion mass spectrometry and statistical analysis, where eight markers related to the pathophysiological process of ZIKV infection were elected and characterized. Among these, Angiotensin (1-7) and Angiotensin I were upregulated under infection, showing an attempt to induce autophagy of the infected cells. However, this finding is concerning about hypertensive individuals under treatment with inhibitors of the Renin-Angiotensin System (RAS), which could reduce this response against the virus and exacerbate the symptoms of the infection. Moreover, one of the most abundant glycosphingolipids in the nervous tissue, Ganglioside GM2, was also elected in the present study as an infection biomarker. Considered an important pathogen receptor at membranes outer layer, this finding represents the importance of gangliosides for ZIKV infection and its association with brain tropism. Furthermore, a series of phosphatidylinositols were also identified as biomarkers, implying a significant role of the PI3K-AKT-mTOR Pathway in this mechanism. Finally, these pathways may also be understood as potential targets to be considered in pharmacological intervention studies on ZIKV infection management.

Fitting The Incidence Data From The City Of Campinas, Brazil, Based On Dengue Transmission Modellings Considering Time-dependent Entomological Parameters

Four time-dependent dengue transmission models are considered in order to fit the incidence data from the City of Campinas, Brazil, recorded from October 1st 1995 to September 30th 2012. The entomological parameters are allowed to depend on temperature and precipitation, while the carrying capacity and the hatching of eggs depend only on precipitation. The whole period of incidence of dengue is split into four periods, due to the fact that the model is formulated considering the circulation of only one serotype. Dengue transmission parameters from human to mosquito and mosquito to human are fitted for each one of the periods. The time varying partial and overall effective reproduction numbers are obtained to explain the incidence of dengue provided by the models.

Schistosomal myeloradiculopathy in a low-prevalence area: 27 cases (14 autochthonous) in Campinas, São Paulo, Brazil

Schistosomal myeloradiculopathy (SMR) is a form of schistosomiasis that is not linked with a high worm burden but rather is found in patients who have been sporadically exposed to Schistosoma mansoni. This paper aims to determine the occurrence of SMR in a low-endemic area with urban transmission in Campinas, São Paulo, Brazil. A retrospective study was performed, identifying confirmed cases in the two largest public hospitals on the region. Patients were diagnosed with SMR using standardised criteria, common clinical parameters, evidence of schistosomal infection and exclusion of other causes of myelopathy. A total of 27 patients were identified; 19 (85.2%) were men and four (14.8%) were women, ranging from 13-57 years of age (mean = 31.2; standard deviation = 12.8). Patients were classified as autochthonous (n = 14; 51.9%) or allochthonous (n = 11; 40.7%) and epidemiological data could not be obtained for two patients (7.4%). The clinical parameters of these patients were not different from previous studies. The sensitivity of serum immune reactions, cerebrospinal fluid immune reactions and parasitological stool examinations in identifying infected individuals was 87.5%, 93.8% and 40%, respectively. The epidemiological importance of these findings and their relationship with the control policies of schistosomiasis are discussed.

INTRODUCTION AND TRANSMISSION OF ZIKA VIRUS IN BRAZIL: NEW CHALLENGES FOR THE AMERICAS.

Campinas, August 27, 2015 n nDear Editor n nIn October 2014 an outbreak of a febrile rash illness of unknown etiology was identified in the State of Rio Grande do Norte, Northeastern Brazil, whose clinical manifestations were low fever or no fever, maculopapular rash, pruritus, arthralgia, and limb edema, lasting 4-7 days. In the following months, similar cases were identified in other States of the region. The initial diagnostic hypotheses of dengue, measles, rubella, enterovirus, and other arbovirus (including Chikungunya) were not confirmed. In early May 2015, Zika virus (ZIKV), an arbovirus which until then had not circulated in Brazil, was confirmed by RT-PCR tests in 15 of 45 samples from patients of two States: Bahia and Rio Grande do Norte. CAMPOS et al. (2015) reported seven confirmed cases of 24 tested samples and ZANLUCA et al. (2015) confirmed eight cases of 21 acute phase serum samples1 , 2. In the following weeks, since the end of May, new autochthonous cases were laboratory confirmed in other States of the Northeastern region (Alagoas, Ceara, Maranhao,Paraiba, Pernambuco, Piaui), Northern region (Para, Roraima) Southeastern region (Sao Paulo and Rio de Janeiro), and Southern region (Parana), showing that the disease has already expanded throughout the Brazilian territory. These results represent not only the first human cases in Brazil, but also the first presumptive vector borne transmission of ZIKV in Continental America and, potentially, the epidemiological trigger for a worldwide epidemic. Previously imported cases of flavivirus infection have been identified in Europe3, and recently, a first exported case of ZIKV to Europe was reported in the new Brazilian scenario of ZIKV expansion4. n nZIKV infection was confirmed in different Brazilian States in a short period of time; some locations were separated by 2300 km away5ZIKV circulation has occurred simultaneously to a dengue epidemic of large proportions in regions dense and chronically infested by Aedes aegypti. The confirmed circulation of Chikungunya virus in some regions of the Brazilian territory, as in other countries of South America and Caribe raises concerns about the implications of the new virus and its co-circulation with other arboviruses in the context of public health. n nThe ZIKV is an arbovirus of the genus Flavivirus belonging to the Flaviviridae family. It was first identified in 1947 in a rhesus monkey sentinel for yellow fever research conducted at the Zika forest in Uganda6 , 7. The disease in humans has been well documented only from the 1960s, and by 2007, when less than 20 laboratory confirmed cases were described8. The ZIKV has been isolated from various species of Aedes mosquitos especially Ae. africanus, Ae. aegypti and Ae. albopictus, all potential vectors. Recent epidemics transmission has been attributed to Ae. hensilli and Ae. Polynesiensis 9 , 10. The sylvatic cycle of viruses is maintained by genusAedes mosquitoes and non-human primates8 and, until recently human beings would be considered only casual hosts. n nThe geographical expansion of ZIKV transmission beyond Asia and Africa has possibly occurred after 2007, when an outbreak hit the Island of Yap, Micronesia, with an estimated infection of 73% of the population and 12% with clinical manifestations11. Since then a spread of the virus to several Pacific islands has been observed, with autochthonous cases reported in New Caledonia, Cook Islands and Easter Island10 , 11. n nSpecial attention should be given to an outbreak in French Polynesia from October 2013 until early 2014 due to a large number of symptomatic patients (more than 29,000 people, or about 10% of the population) and the severe cases, particularly with neurological disorders (including 40 cases of Guillain-Barre syndrome (GBS) and 72 cases of various neurological syndromes), assigned to infection ZIKV10. However, it is noteworthy that a real causal relationship between ZIKV as the etiologic agent of neurological complications (especially those related to immune mechanisms) or neurological conditions resulting from potential association between ZIKV co-circulation and distinct virus serotypes Dengue (serotypes 1 and 3)11 has not yet been well established. n nThe laboratory diagnosis of the ZIKV infection might require the identification by direct methods, such as viral isolation and RT-PCR since there is no serological testing available for specific IgM/IgG antibodies to ZIKV6. There are also specific limitations of serological studies resulting from the possible cross-reactivity with other flaviviruses, among which the dengue virus and yellow fever virus (wild and vaccine virus). This is a very probable scenario in South America and other regions of the world, where there is an endemic circulation of other pathogens like Japanese encephalitis virus and West Nile virus. n nTransmission of Zika virus in Brazil has many concerns: social and ecological context in the Americas, particularly in Brazil favors the spread of arboviruses and the occurrence of severe cases associated with viral co-circulation; the current strategy to combat the vector in most areas seems ineffective; climate and environmental conditions are adequate to the vector activity; crowded cities with intense flow of travelers from around the world makes Brazil not only vulnerable to large outbreaks but also a point of dispersion of cases through the world. Moreover, the widespread presence of Ae. albopictus in the Americas brings concern that the vector becomes a ZIKV very efficient transmitter, further aggravating this complex epidemiological context. Nowadays, the high vector density in Brazil supports the simultaneous circulation of three arboviruses transmitted by Ae. aegypti: dengue, Chikungunyia and Zika. However, this context shows that there is also risk of a potential introduction and/or expansion of other arboviruses, in not endemic areas in the Americas. The recent introduction of ZIKV raises many concerns to the Brazilian health authorities especially about the potential occurrence of severe cases in the future. However, the recent report of a high number of cases presenting neurological syndromes, mostly compatible with GBS, in some Northeastern Brazilian States, has already brought a worrying impact on the health system, despite the fact that further epidemiological information are awaited from ongoing investigation5. n nFrom this, questions as how to structure patient care to address difficulties on clinical and laboratory diagnosis and what will be the implications of co-circulation of ZIKV and other flaviviruses are only some of the too many questions to be answered. The apparent rapid expansion of ZIKV transmission area in Brazil should now be seen as an emergent public health challenge not only to the country, but to the Americas and, to some degree, also to the globe.

Excess of Mortality in Adults and Elderly and Circulation of Subtypes of Influenza Virus in Southern Brazil

Purpose In the elderly population, the influenza infection and its clinical complications are important causes of hospitalization and death, particularly, in longer-lived age. The objective of this study is to analyze the impact of influenza virus circulation on mortality in the elderly and adults, in years with different predominant virus strains. Methods We performed a time trend study to evaluated excess of mortality for pneumonia and influenza, respiratory disease, and all-causes in southern region of Brazil, from 2002 to 2015. After considering other models, we opted for Serfling regression. Excess of death rates per 100,000 inhabitants were analyzed in specific age groups (24–59, 60–69, 70–79, ≥80u2009years) and by year of occurrence. Mortality information were taken from Brazilian Mortality Information System and etiological data were accessed in Sentinel Virological Surveillance database, getting the weekly positivity of the immunofluorescence tests for influenza A (H1N1, H3N2), and B. Results In southern Brazil, there is an evident seasonal pattern of all death outcomes among different age groups in the dry and cold season (April–September). The highest excess mortality rates occurs among older, particularly in years of circulation of influenza AH3N2, especially among people ≥80u2009years, in 2003 and 2007—years of great severity of influenza activity. After 2009, with the introduction of the pandemic influenza AH1N1, we observed a lower impact on the mortality of the elderly compared to <60u2009years. Discussion A cross reactivity antibody response from past exposure probably provided protection against disease in the elderly. Despite not controlling for comorbidities, climate, and vaccination, for the >70u2009years, ratio of respiratory diseases excess mortality rates between AH1N1 (2009) and severe year of H3N2 (2007) shows protection in the pandemic year and great vulnerability during AH3N2 virus predominance. Conclusion The reduced immune response to infection, and to vaccination, and presence of comorbidities recommend a special attention to this age group in Brazil. Besides medical assistance, the timeliness of vaccine campaigns, its composition, and etiological surveillance of respiratory diseases are some of the preventive and public health measures.

Revision of Godartiana Forster (Lepidoptera: Nymphalidae), with the description of a new species from northeastern Brazil

A revision of Godartiana Forster, 1964 (Satyrinae: Euptychiina) is provided, including the description of a new species, G. amadoi Paluch, Zacca & Freitas sp. nov. from Bahia and Pernambuco, northeastern Brazil. Two genera, Cercyeuptychia L. Miller & Emmel, 1971 syn. nov. and Praefaunula Forster, 1964 syn. nov., are herein synonymised with Godartiana, based on morphological and molecular data from mitochondrial gene Cytochrome C Oxidase I and the nuclear genes GAPDH and RpS5. A new taxonomic arrangement is proposed for Godartiana, increasing to five the number of species known in this genus and also synonymising Euptychia liturata Butler, 1867 syn. nov. and E. vesper Butler, 1867 syn. nov. with G. armilla (Butler, 1867) comb. nov. The female genitalia of all species of Godartiana are described and illustrated, information is given on host plants and biology, and the previously unknown immature stages of G. muscosa are described and illustrated.

Respiratory syncytial virus seasonality in Brazil: implications for the immunisation policy for at-risk populations

Respiratory syncytial virus (RSV) infection is the leading cause of hospitalisation for respiratory diseases among children under 5 years old. The aim of this study was to analyse RSV seasonality in the five distinct regions of Brazil using time series analysis (wavelet and Fourier series) of the following indicators: monthly positivity of the immunofluorescence reaction for RSV identified by virologic surveillance system, and rate of hospitalisations per bronchiolitis and pneumonia due to RSV in children under 5 years old (codes CID-10 J12.1, J20.5, J21.0 and J21.9). A total of 12,501 samples with 11.6% positivity for RSV (95% confidence interval 11 - 12.2), varying between 7.1 and 21.4% in the five Brazilian regions, was analysed. A strong trend for annual cycles with a stable stationary pattern in the five regions was identified through wavelet analysis of the indicators. The timing of RSV activity by Fourier analysis was similar between the two indicators analysed and showed regional differences. This study reinforces the importance of adjusting the immunisation period for high risk population with the monoclonal antibody palivizumab taking into account regional differences in seasonality of RSV.