Researchers report detailed analysis of heart damage caused by yellow fever virus

To fill the knowledge gap on yellow fever (YF), a group of Brazilian researchers affiliated with the Department of Pathology of the Faculty of Medicine of the University of São Paulo (FM-USP), at the Hospital das Clínicas ( HC, the hospital complex managed by FM -USP), the Institute of Cardiology (InCor, linked to HC) and the Emílio Ribas Institute of Infectious Diseases (IIER) studied the pathogenesis of cardiac damage associated with yellow fever.

The team was led by Fernando Rabioglio Giugni, cardiologist, and Amaro Nunes Duarte-Neto, infectious disease specialist and pathologist; both work at FM-USP.

“There is no specific treatment for yellow fever yet. Patients receive intensive care support, including blood transfusions, mechanical ventilation and treatment for seizures, but the mortality rate in severe cases is high , above 35%,” Giugni said.

The team’s article, recently published in the journal eBioMedicine, presents a retrospective autopsy study of cases from the Brazilian yellow fever epidemic of 2017 to 2019, with detailed descriptions of clinical and laboratory data, as well as macroscopic and microscopic aspects of cardiac tissue from patients who died during this period in the State of São Paulo. It was the worst outbreak of yellow fever reported worldwide since the start of the 21st century, and at the time, HC and IIER specialized in treating the disease.

The yellow fever virus mainly affects the liver, causing severe acute hepatitis by direct damage to hepatocytes in 5 to 30% of cases. Hepatitis in yellow fever can be fulminant, with symptoms including nausea, vomiting, jaundice, hemorrhagic changes (mucosal, gastrointestinal, pulmonary, and cerebral hemorrhages), and hepatic coma.

Other organs besides the liver are also affected by yellow fever, including the kidneys, brain, lungs, spleen, pancreas and heart. Exactly how the virus damages these organs is poorly understood. For example, patients with yellow fever are known to have refractory hypotension (shock) and, in severe cases, cardiac arrhythmias such as bradycardia (slow heart rate), described as accompanied by fever by the doctor at the hospital. Louisiana Jean Charles Faget (1818-1884) in the mid-19th century (and therefore known as Faget sign).

Discoveries

The main problems observed by the researchers were myocardial fibrosis and hypertrophy of cardiomyocytes (heart muscle cells) in 93.2% of cases, and (in 91.8%) alterations of the vascular endothelium, the inner lining blood vessels, causing bleeding, swelling and small blood clots in the heart. They also detected fiber necrosis in 68.5%, viral myocarditis in 12.3%, and secondary myocarditis due to bacteria and fungi in 6.8%.

The cardiac conduction system, which generates the electrical stimulus that causes the heart to beat properly, was impaired in 11.0%, with edema, hemorrhages, and inflammation, demonstrating for the first time the anatomical substrate of the arrhythmias found in human yellow fever. .

Yellow fever viral RNA was detected in 95.7% of cases using advanced molecular biology techniques, as well as viral antigens in endothelial and inflammatory cells, indicating direct action of the virus on heart tissue. The main inflammatory cells found in cases of myocarditis were activated macrophages.

Proteomic analysis showed higher levels of interferon gamma-induced protein 10 (IP-10, also known as CXCL-10), a chemokine produced by macrophages that attracts more inflammatory cells to the site of any injury caused by the virus. High levels of this protein have previously been described in patients with COVID-19, dengue and Zika, and associated with a worse prognosis.

“The importance of this research is that it allows us to better understand what happens to the hearts of patients with severe yellow fever and of subjects with severe reactions to the vaccine, given that the alterations in question may be masked or under -estimated due to fulminant hepatitis typical of yellow fever. disease,” Duarte-Neto said.

Myocardial injury is common in severe cases of yellow fever, due to multifactorial mechanisms that include direct virus-induced damage, endothelial cell damage, and an inflammatory response (myocarditis).

“With this understanding, it is possible to implement diagnostic and therapeutic measures to prevent and treat yellow fever-related cardiac damage,” he said.

Re-emerging disease

A total of 696 cases of yellow fever were reported in the state of São Paulo between 2017 and 2019, with 232 deaths (33.3%). The main factors that contributed to the establishment of the epidemic were environmental changes, the expansion of urban areas into the remnants of the Atlantic rainforest where circulation of the virus increased, and unvaccinated people going into the forest.

Yellow fever is now considered a re-emerging disease in Brazil (and Latin America in general). Vaccination is recommended nationwide, but a significant number of susceptible people have not received the vaccine, particularly in densely populated, non-endemic urban areas, which could suffer from outbreaks if the virus spreads rapidly as at São Paulo, and even throughout the country. southeast of Brazil, at the end of the 2010s.

The disease has two main forms of transmission. In the sylvatic (wild) transmission cycle, humans are infected by the bite of Haemagogus and Sabethes mosquitoes. In the urban transmission cycle, the virus is transmitted by the Aedes aegypti mosquito. The 2017–2019 outbreak in São Paulo was considered an epidemic due to sylvatic transmission.

Rare cases of complications following vaccination are called yellow fever vaccine-associated viscerotropic diseases (YEL-AVD), generally associated with the 17DD substrains of the vaccine used in South America.