Genetic factors associated with acute viral bronchiolitis are identified

Research conducted in Brazil could help develop tests to estimate progression of the disease, which is the leading cause of hospitalization in the first year of life.

By Peter Moon  |  Agência FAPESP – A scientific study conducted at the University of Campinas (UNICAMP) in São Paulo State, Brazil, has identified genetic factors associated with the severity of acute viral bronchiolitis. The study was supported by FAPESP. Its results were published in the March 1, 2018, issue of the journal Gene.

“Detecting genetic associations in cases of acute viral bronchiolitis is the first step toward the development of tests to predict the possible clinical outcome for each patient diagnosed with the disease soon after arrival at the emergency room,” said Fernando Augusto de Lima Marson, a researcher at UNICAMP’s Medical School (FCM) and one of the authors of the article.

According to José Dirceu Ribeiro, principal investigator for the study and a professor at FCM-UNICAMP, children can be predisposed to acute viral bronchiolitis by various risk factors, such as prematurity, a history of lung disease, and passive smoking. “On the other hand, a very significant proportion of patients present with no risk factors, and the question arises in these cases of how to explain progression of the disease to its most severe form,” Ribeiro said.

The new study set out to find correlations between genetic factors and the severest forms of acute viral bronchiolitis in patients not classified in any risk groups. 

The disease is most common in the first year of life, Ribeiro recalls. It is the leading cause of hospitalization during this period of infancy worldwide. 

It is an infection of the respiratory tract that causes acute inflammatory damage to the bronchioles, tiny airways that lead to the lungs. Most cases are mild and do not have major consequences, but 1%-3% require hospitalization, with some patients needing supplemental oxygen. A smaller proportion require ICU treatment including mechanical ventilation. 

To investigate the existence of possible genetic factors that may influence the severity of the disease, the researchers studied 181 children admitted over a period of two years to three hospitals in the Campinas area. All were diagnosed with acute viral bronchiolitis and given oxygen therapy. Screening was conducted at UNICAMP’s teaching hospital (Hospital das Clínicas), the Sumaré State Hospital, and Vera Cruz Hospital.

The researchers first took samples of the patients’ nasal secretions to determine the type of virus that had caused bronchiolitis in each case. As expected, in most cases, it was respiratory syncytial virus (RSV). More specifically, infection by RSV accounted for 69.9% of the cases, while rhinovirus accounted for 26.5%.

The researchers also evaluated all 181 children to find out if they fell within one or more risk groups for acute viral bronchiolitis. The result of this analysis was revealing in that 131, or 72%, were not part of any risk group.

Molecular biology and statistical techniques were used to study and compare the patients’ DNA. Specific genetic markers were sought, especially single-nucleotide polymorphisms (SNPs), a type of DNA sequence variation that accounts for over 90% of genetic variation in the human genome. 

In the statistical treatment of the data, patient outcomes were compared, and polymorphism frequency was compared between patients and a control group comprising 536 healthy individuals aged 19-25, randomly invited and with no personal or family history of lung disease.

Polymorphism frequencies were also analyzed for each type of virus, including RSV subtypes A and B, as well as rhinovirus, and possible cases of virus co-detection were identified.

“Our study focused on the genetic factors that might be associated with the severity of acute viral bronchiolitis,” Marson said. “It provides evidence of a link between the patient’s genetic predisposition and the severity of the disease. As far as we’re aware, it’s the first study worldwide to show this in such detail, including a large number of genetic variants.”

Some genes are indeed associated with the presence of specific viruses that can cause the disease. The researchers at UNICAMP found a link between the SNP rs2107538*CCL5 and bronchiolitis caused by RSV and RSV subtype A and a link between the SNP rs1060826*NOS2 and bronchiolitis caused by rhinovirus.

“The SNPs rs4986790*TLR4, rs1898830*TLR2 and rs2228570*VDR were associated with very severe cases of the disease, which progressed to a fatal outcome. The SNP rs7656411*TLR2 was associated with the need for oxygen supplementation, while rs352162*TLR9, rs187084*TLR9 and rs2280788*CCL5 were associated with cases in which ICU admission was required. Finally, rs1927911*TLR4, rs352162*TLR9 and rs2107538*CCL5 were associated with the need for mechanical ventilation,” Marson said.

The authors of the study stress the importance of replication using other datasets. Nevertheless, they consider the results highly promising.

“Medicine is advancing toward the development of therapies tailored to the needs of each patient,” Marson said. “In this context, the identification of SNPs associated with the disease in question could provide a target for genetic therapy, so that treatments and management strategies can be developed for precision medicine and preventive medicine, respectively.”

The article “Association between single nucleotide polymorphisms in TLR4, TLR2, TLR9, VDR, NOS2 and CCL5 genes with acute viral bronchiolitis” (doi: https://doi.org/10.1016/j.gene.2017.12.022) by Alfonso Eduardo Alvarez, Fernando Augusto Lima Marson, Carmen Sílvia Bertuzzo, Juliana Cristina Santiago Bastos, Emilio Carlos Elias Baracat, Marcelo Barciel Brandão, Antônia Teresinha Tresoldi, Mariana Tresoldi das Neves Romaneli, Celize Cruz Bresciani Almeida, Therezinha de Oliveira, Patricia Godano Schlodtmann, Ester Corrêa, Maria Luísa Ferreira de Miranda, Marcelo Conrado dos Reis, José Vicente De Pieri, Clarice Weis Arns and José Dirceu Ribeiro can be retrieved from: sciencedirect.com/science/article/pii/S0378111917310752.