Chikungunya in Brazil: An epidemic of high cost for private healthcare, 2017.

OBJECTIVE: We evaluated the impact of direct and indirect medical costs incurred through chikungunya infections in patients treated in Fortaleza, Brazil. METHODS: Cross-sectional study about the cost of illness. The valuation method of medical costs was based on the micro-costing approach (bottom-up). The study was carried out in a large general hospital of the private health network. The study population consisted of patients treated as suspected cases of chikungunya and hospital professionals who applied for sick leave due to chikungunya. RESULTS: In 2017, there were 2683 patients treated at this hospital who incurred an estimated cost of $383,514.40. From this amount, $174,322.91 (45.5%) were expended on emergency care, $194,700.59 (50.8%) on hospitalisations. 123 hospital professionals were infected with chikungunya and sick leave duration ranged between 1 and 19 days. Health professionals generated 746 days of absence and an amount of $14,490.90 due to absenteeism from work related to chikungunya. 31 symptoms were reported, especially arthralgia (91.1%) and fever (79.4%). There was a predominance of females (58.8%) and the age group of 20-39 years (42.1%). CONCLUSION: The average cost of admissions was over $2400. Considering the epidemic potential of chikungunya, our data indicate the huge economic burden of this disease to healthcare units in the presence of epidemics. Economic factors, added to the loss of life and the consequences of chronic chikungunya, make this disease a real scourge for countries with fewer material resources.

Seroprevalence, spatial dispersion and factors associated with flavivirus and chikungunha infection in a risk area: a population-based seroprevalence study in Brazil.

BACKGROUND: The State of Ceará, in Northeastern Brazil, suffers from a triple burden of arboviruses (dengue, Zika and chikungunya). We measured the seroprevalence of chikungunya, dengue and Zika and its associated factors in the population of Juazeiro do Norte, Southern Ceará State, Brazil. METHODS: A cross-sectional study of analytical and spatial analysis was performed to estimate the seroprevalence of dengue, Zika and chikungunya, in the year 2018. Participants were tested for IgM and IgG against these three viruses. Those with IgM and/or IgG positive tests results were considered positive. Poisson regression was used to analyze the factors associated with positive cases, in the same way that the spatial analysis of positive cases was performed to verify whether the cases were grouped. RESULTS: Of the 404 participants, 25.0% (103/404) were positive for CHIKV, 92.0% (373/404) for flavivirus (dengue or Zika) and of these, 37.9% (153/404) samples were classified as probable dengue infection. Of those who reported having had an arbovirus in the past, positive CHIKV cases had 58.7% arthralgia (PR = 4.31; 95% CI: 2.06-9.03; p = 0.000) mainly in the hands, ankles and feet. Age over 60 years had a positive association with cases of flavivirus (PR = 1.29; 95% CI: 1.09-1.54; p = 0.000). Fever, muscle pain, joint pain and skin rash were the most reported symptoms (46.1, 41.0, 38.3 and 28.41%, respectively). The positive cases of chikungunya and dengue or Zika were grouped in space and the city center was most affected area. CONCLUSIONS: Four years after the introduction of CHIKV, where DENV has been in circulation for over 30 years, 1/4 of the population has already been exposed, showing the extent of the epidemic. The measured prevalence was much higher than that reported by local epidemiological surveillance.

ZIKV-Specific NS1 Epitopes as Serological Markers of Acute Zika Virus Infection.

BACKGROUND: Zika virus (ZIKV) infections have reemerged as a global health issue due to serious clinical complications. Development of specific serological assays to detect and differentiate ZIKV from other cocirculating flaviviruses for accurate diagnosis remains a challenge. METHODS: We investigated antibody responses in 51 acute ZIKV-infected adult patients from Campinas, Brazil, including 7 pregnant women who later delivered during the study. Using enzyme-linked immunosorbent assays, levels of antibody response were measured and specific epitopes identified. RESULTS: Several antibody-binding hot spots were identified in ZIKV immunogenic antigens, including membrane, envelope (E) and nonstructural protein 1 (NS1). Interestingly, specific epitopes (2 from E and 2 from NS1) strongly recognized by ZIKV-infected patients' antibodies were identified and were not cross-recognized by dengue virus (DENV)-infected patients' antibodies. Corresponding DENV peptides were not strongly recognized by ZIKV-infected patients' antibodies. Notably, ZIKV-infected pregnant women had specific epitope recognition for ZIKV NS1 (amino acid residues 17-34), which could be a potential serological marker for early ZIKV detection. CONCLUSIONS: This study identified 6 linear ZIKV-specific epitopes for early detection of ZIKV infections. We observed differential epitope recognition between ZIKV-infected and DENV-infected patients. This information will be useful for developing diagnostic methods that differentiate between closely related flaviviruses.

Excess Mortality and Causes Associated with Chikungunya, Puerto Rico, 2014-2015.

During 2014-2015, a total of 31 deaths were associated with the first chikungunya epidemic in Puerto Rico. We analyzed excess mortality from various causes for the same months during the previous 4 years and detected 1,310 deaths possibly attributable to chikungunya. Our findings raise important questions about increased mortality rates associated with chikungunya.

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

Background: Zika virus (ZIKV) infections have been linked to different levels of clinical outcomes, ranging from mild rash and fever to severe neurological complications and congenital malformations. Methods: We investigated the clinical and immunological response, focusing on the immune mediators profile in 95 acute ZIKV-infected adult patients from Campinas, Brazil. These patients included 6 pregnant women who later delivered during the course of this study. Clinical observations were recorded during hospitalization. Levels of 45 immune mediators were quantified using multiplex microbead-based immunoassays. Results: Whereas 11.6% of patients had neurological complications, 88.4% displayed mild disease of rash and fever. Several immune mediators were specifically higher in ZIKV-infected patients, and levels of interleukin 10, interferon gamma-induced protein 10 (IP-10), and hepatocyte growth factor differentiated between patients with or without neurological complications. Interestingly, higher levels of interleukin 22, monocyte chemoattractant protein 1, TNF-α, and IP-10 were observed in ZIKV-infected pregnant women carrying fetuses with fetal growth-associated malformations. Notably, infants with congenital central nervous system deformities had significantly higher levels of interleukin 18 and IP-10 but lower levels of hepatocyte growth factor than those without such abnormalities born to ZIKV-infected mothers. Conclusions: This study identified several key markers for the control of ZIKV pathogenesis. This will allow a better understanding of the molecular mechanisms of ZIKV infection in patients.

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.

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.

Epidemiology and Economic Burden of Chikungunya: A Systematic Literature Review.

Chikungunya (CHIK) is a re-emerging viral infection endemic in tropical and subtropical areas. While the typical clinical presentation is an acute febrile syndrome, long-term articular complications and even death can occur. This review characterizes the global epidemiological and economic burden of chikungunya. The search included studies published from 2007 to 2022 in MEDLINE, Embase, LILACS, and SciELO for a thorough evaluation of the literature. Rayyan software was used for data analysis, and data were summarized descriptively and reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Seventy-six publications were included. Chikungunya is widely distributed in the tropics, including Africa, Asia, South America, and Oceania/the Pacific Islands, and co-circulates with other simultaneous arboviruses such as DENV, ZIKV, and YFV. Chikungunya infection can lead to chronic articular manifestations with a significant impact on the quality of life in the long term. In addition, it generates absenteeism and economic and social losses and can cause fatal infections in vulnerable populations, mainly in high-risk patients with co-morbidities and at the extremes of age. Reported costs associated with CHIKV diseases are substantial and vary by region, age group, and public/private delivery of healthcare services. The chikungunya disease burden includes chronicity, severe infections, increased hospitalization risks, and associated mortality. The disease can impact the economy in several spheres, significantly affecting the health system and national economies. Understanding and measuring the full impact of this re-emerging disease is essential.

Genomic epidemiology unveils the dynamics and spatial corridor behind the Yellow Fever virus outbreak in Southern Brazil.

Despite the considerable morbidity and mortality of yellow fever virus (YFV) infections in Brazil, our understanding of disease outbreaks is hampered by limited viral genomic data. Here, through a combination of phylogenetic and epidemiological models, we reconstructed the recent transmission history of YFV within different epidemic seasons in Brazil. A suitability index based on the highly domesticated Aedes aegypti was able to capture the seasonality of reported human infections. Spatial modeling revealed spatial hotspots with both past reporting and low vaccination coverage, which coincided with many of the largest urban centers in the Southeast. Phylodynamic analysis unraveled the circulation of three distinct lineages and provided proof of the directionality of a known spatial corridor that connects the endemic North with the extra-Amazonian basin. This study illustrates that genomics linked with eco-epidemiology can provide new insights into the landscape of YFV transmission, augmenting traditional approaches to infectious disease surveillance and control.

The emergence of novel SARS-CoV-2 variant P.1 in Amazonas (Brazil) was temporally associated with a change in the age and sex profile of COVID-19 mortality: A population based ecological study.

BACKGROUND: Since the end of 2020, there has been a great deal of international concern about the variants of SARS-COV-2 B.1.1.7, identified in the United Kingdom; B.1.351 discovered in South Africa and P.1, originating from the Brazilian state of Amazonas. The three variants were associated with an increase in transmissibility and worsening of the epidemiological situation in the places where they expanded. The lineage B.1.1.7 was associated with the increase in case fatality rate in the United Kingdom. There are still no studies on the case fatality rate of the other two variants. The aim of this study was to analyze the mortality profile before and after the emergence of the P.1 strain in the Amazonas state. METHODS: We analyzed data from the Influenza Epidemiological Surveillance Information System, SIVEP-Gripe (Sistema de Informação de Vigilância Epidemiológica da Gripe), comparing two distinct epidemiological periods: during the peak of the first wave, between April and May 2020, and in January 2021 (the second wave), the month in which the new variant came to predominate. We calculated mortality rates, overall case fatality rate and case fatality rate among hospitalized patients; all rates were calculated by age and gender and 95% confidence intervals (95% CI) were determined. FINDINGS: We observed that in the second wave there were a higher incidence and an increase in the proportion of cases of COVID-19 in the younger age groups. There was also an increase in the proportion of women among Severe Acute Respiratory Infection (SARI) cases from 40% (2,709) in the first wave to 47% (2,898) in the second wave and in the proportion of deaths due to COVID-19 between the two periods varying from 34% (1,051) to 47% (1,724), respectively. In addition, the proportion of deaths among people between 20 and 59 years old has increased in both sexes. The case fatality rate among those hospitalized in the population between 20 and 39 years old during the second wave was 2.7 times the rate observed in the first wave (female rate ratio = 2.71; 95% CI: 1.9-3.9], p <0.0001; male rate ratio = 2.70, 95%CI:2.0-3.7), and in the general population the rate ratios were 1.15 (95% CI: 1.1-1.2) in females and 0.78 (95% CI: 0.7-0.8) in males]. INTERPRETATION: Based on this prompt analysis of the epidemiological scenario in the Amazonas state, the observed changes in the pattern of mortality due to COVID-19 between age groups and gender simultaneously with the emergence of the P.1 strain suggest changes in the pathogenicity and virulence profile of this new variant. Further studies are needed to better understanding of SARS-CoV-2 variants profile and their impact for the health population. FUNDING: There was no funding for this study.

A prospective, multicentre, cohort study to assess the incidence of dengue illness in households from selected communities in Brazil (2014-2018).

OBJECTIVES: To estimate the incidence of dengue infection across geographically distinct areas of Brazil. METHODS: This prospective, household-based, cohort study enrolled participants in five areas and followed them up for up to 4 years (2014-2018). Dengue seroprevalence was assessed at each scheduled visit. Suspected dengue cases were identified through enhanced passive and active surveillance. Acute symptomatic dengue infection was confirmed through reverse-transcriptase quantitative polymerase chain reaction in combination with an antigenic assay (non-structural protein 1) and serology. RESULTS: Among 3300 participants enrolled, baseline seroprevalence was 76.2%, although only 23.3% of participants reported a history of dengue. Of 1284 suspected symptomatic dengue cases detected, 50 (3.9%) were laboratory-confirmed. Based on 8166.5 person-years (PY) of follow-up, the incidence of laboratory-confirmed symptomatic infection (primary endpoint) was 6.1 per 1000 PY (95% confidence interval [CI]: 4.5, 8.1). Incidence varied substantially in different years (1.8-7.4 per 1000 PY). The incidence of inapparent primary dengue infection was substantially higher: 41.7 per 1000 PY (95% CI: 31.1, 54.6). CONCLUSIONS: Our findings, highlighting that the incidence of dengue infection is underestimated in Brazil, will inform the design and implementation of future dengue vaccine trials. CLINICAL TRIAL REGISTRATION: NCT01751139.

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.

Estimated mortality rate and leading causes of death among individuals with chikungunya in 2016 and 2017 in Brazil.

INTRODUCTION: In 2014, the first cases of autochthonous chikungunya (CHIK) were recorded in Brazil. Lethality associated with this disease is underestimated. Thus, this study aimed to analyze the causes of death among individuals with CHIK in Brazil. METHODS: A descriptive observational study was conducted on individuals with CHIK who died within 6 months from symptom onset. Data pairing between the Information System for Notifiable Diseases and the Mortality Information System was performed. Deaths were classified according to case confirmation criterion, mention of CHIK in the death certificates (DCs), and disease phase. The lethality rate per 1,000 cases was corrected for underreporting and was estimated according to region, sex, age, years of education, race/color, and cause groups. RESULTS: We identified 3,135 deaths (mention of CHIK in the DCs, 764 [24.4%]). In 17.6% of these cases, CHIK was the underlying cause. Most deaths occurred in the acute (38.1%) and post-acute (29.6%) phases. The corrected LR (5.7; x1,000) was 6.8 times higher than that obtained from the Information System for Notifiable Diseases (0.8). The highest corrected LRs were estimated for among individuals living in the Northeast region (6.2), men (7.4), those with low years of education and those aged <1 year (8.6), 65-79 years (20.7), and ≥80 years (75.4). CONCLUSIONS: The LR of CHIK estimates based on information system linkage help to reveal the relevance of this disease as the direct cause or as a cause associated with serious or fatal events, provide timely interventions, and increase the knowledge about this disease.

Tracking excess deaths associated with the COVID-19 epidemic as an epidemiological surveillance strategy-preliminary results of the evaluation of six Brazilian capitals.

INTRODUCTION: In March 2020, the World Health Organization declared the coronavirus disease (COVID-19) outbreak a pandemic. In Brazil, 110 thousand cases and 5,901 deaths were confirmed by the end of April 2020. The scarcity of laboratory resources, the overload on the service network, and the broad clinical spectrum of the disease make it difficult to document all the deaths due to COVID-19. The aim of this study was to assess the mortality rate in Brazilian capitals with a high incidence of COVID-19. METHODS: We assessed the weekly mortality between epidemiological week 1 and 16 in 2020 and the corresponding period in 2019. We estimated the expected mortality at 95% confidence interval by projecting the mortality in 2019 to the population in 2020, using data from the National Association of Civil Registrars (ARPEN-Brasil). RESULTS: In the five capitals with the highest incidence of COVID-19, we identified excess deaths during the pandemic. The age group above 60 years was severely affected, while 31% of the excess deaths occurred in the age group of 20-59 years. There was a strong correlation (r = 0.94) between excess deaths and the number of deaths confirmed by epidemiological monitoring. The epidemiological surveillance captured only 52% of all mortality associated with the COVID-19 pandemic in the cities examined. CONCLUSIONS: Considering the simplicity of the method and its low cost, we believe that the assessment of excess mortality associated with the COVID-19 pandemic should be used as a complementary tool for regular epidemiological surveillance.

Biological view of vaccination described by mathematical modellings: from rubella to dengue vaccines.

The only rubella vaccine available in North America is the RA27/3 strain (isolated from the kidney of a rubella-infected fetus and attenuated) licensed in 1979, which substituted HPV77/DE5 strain vaccine due to concerns about waning immunity. The first dengue vaccine (Dengvaxia CYDTDV) was first registered in Mexico in December, 2015, which is a live recombinant tetravalent dengue vaccine. Rubella vaccine was applied since 1969, but tetravalent dengue vaccine is being used in large scale nowadays. In the past, based on unavailable information regarded to rubella vaccine, mathematical models were used to design vaccination schemes in order to avoid congenital rubella syndrome (CRS). Currently, knowing that vaccine does not result in CRS, rubella vaccination is modelled as usual childhood infection. This experience of updated biological knowledge that influenced mathematical modellings of rubella vaccination is taken into account to reflect about the tetravalent dengue vaccine. We also address a discussion about the security of vaccination strategies.

Excess deaths associated with the 2014 chikungunya epidemic in Jamaica.

Although traditionally chikungunya virus is considered non-fatal, recent studies suggest that there may be in fact underreporting of deaths in some situations. A major chikungunya epidemic hit Jamaica in 2014 but no chikungunya-associated deaths were reported. We assessed the excess of all-cause deaths during this epidemic. Excess deaths were estimated by difference between observed and expected mortality based on the average age-specific mortality rate of 2012-2013, using the 99% confidence interval. There was an excess of 2,499 deaths during the epidemic (91.9/100,000 population), and a strong positive correlation between the monthly incidence of chikungunya and the excess of deaths (Rho = 0.939, p < 0.005). No significant concomitant epidemiological or climatic phenomenon occurred. Chikungunya is a major contributor to morbidity during epidemics and may be an unrecognized cause of death. Thus, it is urgent to review clinical protocols and improve the investigations of specific-cause deaths during chikungunya epidemics. Excess deaths could be a strategic tool for epidemiological surveillance.

Excess mortality profile during the Asian genotype chikungunya epidemic in the Dominican Republic, 2014.

Background: In 2014 there was a large chikungunya epidemic in the Dominican Republic, with 539 099 reported cases and 6 deaths. Although chikungunya is considered a low-mortality disease, studies have suggested this is an underestimation. This study assessed deaths associated with the epidemic. Methods: Mortality data were obtained from the National Statistics Office, the surveillance system for acute febrile illnesses, and the National Epidemiological Surveillance System. Expected all-cause mortality by age group was estimated using the years 2010-2012 as the baseline. The excess deaths were calculated as the difference between observed and expected deaths during the epidemic. Results: The mortality rate increased during the chikungunya epidemic in 2014. There was a strong correlation between monthly excess of deaths and chikungunya cases (Pearson's r=0.89). There was an excess of deaths (>99% confidence interval) among individuals <5 y and >40 y of age. The mortality rates were higher among the elderly. The death excess was 2853. Correcting for the estimated underreporting, there were 4952 deaths during the chikungunya epidemic (49.8 deaths/100 000 population). Conclusion: This study suggests that chikungunya is an important cause of death (underlying or contributing). It is urgent to review clinical protocols and investigate the causes associated with deaths during chikungunya epidemics.