Study shows higher risk of death from chikungunya even after disease crisis

Since the beginning of the year, infections caused by the Aedes aegypt mosquito, such as dengue and chikungunya, have been on the rise. In recent weeks, Acre, Minas Gerais, Goiás and the Federal District have declared a state of emergency following an increase in the number of dengue cases, requiring extra care with the mosquito. Other cities are seeing the numbers rise not only for this disease, but also for chikungunya. The State of São Paulo is facing a 26% increase in the number of chikungunya cases this year. Published in the journal The Lancet Infectious Diseases, a study investigated the risk of death in people infected with chikungunya two years after the first symptoms of the disease. By using a sample of the Brazilian population between 2015 and 2018, the main evidence of the research, according to one of the study's researchers, Thiago Cerqueira, "was to show the persistence of the risk of death after chikungunya up to three months after the onset of symptoms, beyond the acute phase of the disease, which is the first 14 days".

Previous research has assessed complications following infection and showed the risk of severity when associated with the presence of other chronic conditions, especially diabetes. Other studies have investigated the excess mortality caused by complications of the disease. However, no studies were found comparing the risk of death between people exposed or not exposed to the virus.

Led by researchers from the Center for Data and Knowledge Integration for Health (Cidacs) and the Precision Medicine and Public Health Laboratory (MeSP2), both at Fiocruz Bahia, the study showed evidence of an increased risk of death even after the period of acute infection by the chikungunya virus. According to Thiago, "generally, the most striking feature of chikungunya is joint pain, which is often the only condition considered by health professionals. The research reveals and quantifies possible complications after the disease, pointing to the need for a more attentive approach to cases of the disease," he noted.

In this study, evidence was presented on the increased risk of natural mortality, and also an increased risk of death associated with other illnesses within 84 days of the onset of symptoms. For Thiago, "in the Brazilian scenario facing a large wave of dengue, chikungunya should not be forgotten. The guidelines should be updated to indicate the potential for metabolic and cardiovascular complications, as well as musculoskeletal complications [related to muscles and bones], with special attention to the first 12 weeks of the onset of symptoms."

The first vaccine for the chikungunya virus was approved in the USA at the end of 2023, but there is still no forecast for it to begin being used in Brazil. Additionally, there are no specific antivirals, and antibody-based therapeutic interventions for the chikungunya virus remain under development. This also points to the need for the development of specific drugs and vaccines for chikungunya and for access to these advances in countries with recurrent outbreaks of the disease. As a limitation of this study, Thiago emphasized that it was not possible to assess "the cases that required hospitalization but did not evolve to death, which may have underestimated the impact of chikungunya".

Risk of death

In this part of the study, the risk of death in people with the disease caused by the chikungunya virus was compared with those without the disease, from 2015 to 2018. When analyzing the data, the research team noticed an increased risk of death up to 84 days of the first symptoms of the infection.

Infected people had an 8.4 times greater risk of death than uninfected people between 1 and 7 days. Between 57 and 84 days, the risk decreased to 2.26 times higher than people without the disease. Thereafter, the risk came near 1, meaning that there was no significant difference in the risk of death between the exposed and unexposed groups during this period. In the analysis of this study and the available data, in a scenario with 100,000 sick people, around 170 more deaths are expected in the first 84 days than in a context without the disease.

When the specific causes of death of these people who had been infected by the virus were studied, a higher mortality associated with diabetes and ischemic heart disease was observed up to the first 28 days, and remained significantly high up to 84 days for ischemic heart disease and up to 168 days for diabetes.

Analysis of the number of deaths between 2015 and 2018

In this other part of the study, between 2015 and 2018, the data of 1,933 people who had the chikungunya virus disease and died in an average time of 294 days, less than a year, were analyzed. Of the cases of natural death, the risk was higher between the first and seventh day of the onset of symptoms of the virus, with a risk 8.75 times higher compared to other periods, decreasing to 1.59 between 57 and 84 days.

For the secondary outcomes, the risk of death within 28 days of the onset of chikungunya symptoms was generally associated with a higher risk of diabetes, at 8.43 times higher than cerebrovascular disease, at 2.73, and ischemic heart disease, at 2.38. There was no evidence of increased risk in subsequent periods between 85 and 168 days for these secondary outcomes.

Similar to the comparative analysis between sick and non-sick people, the analysis carried out with follow-up data on the 1,933 deaths showed an increased relative risk of all-cause natural mortality within 84 days of the initial symptoms.

It is not possible to say that the numbers of deaths from other diseases are only related to the Chikungunya virus, as there are several other variables that could not be analyzed in this study. However, the increased risk of mortality in all age groups, and especially in the first 84 days, reinforces the need for health professionals to closely monitor cases of cardiovascular, neurological, renal and metabolic disorders and other serious clinical conditions linked to systemic diseases and involvement of specific organs, allowing for early detection and prevention of complications and deaths.

Although there is no definitive explanation of the specific mechanisms that increase the risk of mortality in cases of chikungunya infection, it should be recognized, as Thiago mentioned, the existence of "some mechanisms common to various viral infections", which can trigger serious complications that can lead to death. Therefore, it is suggested that greater attention be paid to cases of these diseases, as well as ongoing research to better understand the mechanisms that increase the risk of mortality.

Conducting and data of the study

In this study, data on notifications and laboratory analyses of outcomes for chikungunya, dengue and Zika diseases were linked, and only data from people infected with chikungunya were used for this investigation. Data from the period from January 1, 2015 to December 31, 2018 was used. Two methods were used, the first, a retrospective cohort comparing the risk of death between people exposed to the virus and those not exposed over a period of up to two years after infection. The second, a self-controlled case series, which followed the same time frame as the previous method, but only included people who died after having the disease, comparing the risk of death in different periods in relation to the date of the first symptoms.

143,787 cases of diseases caused by the chikungunya virus between 2015 and 2018 were included. Of the patients, 1,933 died some time after the disease. There were two mortality outcomes: primary, due to natural causes, and secondary, related to deaths associated with specific causes, including ischemic heart diseases – those affecting the arteries and preventing the passage of blood, oxygen and necessary nutrients – diabetes and cerebrovascular diseases.

The study used data from the cohort of 100 million Brazilians, a scientific innovation that includes data on more than 130 million Brazilians from the Single Registry for Social Programs (Cadastro Único para Programas Sociais – CadÚnico). For this study, CadÚnico data was linked to data from the National Information System on Notifiable Diseases (Sinan) and the Mortality Information System (SIM).