London School of Hygiene & Tropical Medicine

Genome sequencing has shed light on the re-emergence of the bacterium that causes yaws, a neglected tropical disease of the skin, bones and joints, according to new research published in Lancet Microbe.

The study was conducted by researchers at the London School of Hygiene & Tropical Medicine (LSHTM), the Wellcome Sanger Institute, the Fight Aids and Infections Disease Foundation, Spain, the University of Washington and the University of Papua New Guinea.

Following a 2013 mass drug administration (MDA) campaign that aimed to eliminate the disease on Lihir Island, Papua New Guinea, cases of Yaws started increasing after two years. To find out why, the researchers sequenced the genetic information of bacteria from 20 swab samples taken during the follow up of the MDA campaign.

Rather than re-emergence being due to a single source, missed case, or reintroduction, the researchers found it was caused by at least three distinct types of the bacteria that causes Yaws – likely due to latent infections in asymptomatic individuals who didn’t receive treatment.

Additionally, a small proportion of the bacteria were found to be resistant to azithromycin, the first time any such resistance had been seen.

This has important implications for disease control, leading the researchers to recommend employing strategies to maximise MDA population coverage to reduce the number of people who are missed by these treatments who may have latent infections. They also recommend intensive post-MDA surveillance for detection of “the last yaws cases” and to control onward transmission of new infections.

Yaws, caused by the bacterium Treponema pallidum subspecies pertenue (TPP), can lead to chronic disfigurement and disability. Most commonly affecting children, infection with the bacteria results in stigmatising and debilitating ulcers. Despite global efforts, yaws remains common in tropical areas in some of the world’s poorest countries, affecting millions of people.

The World Health Organisation (WHO) is currently carrying out campaigns to eradicate the disease using Mass Drug Administration (MDA) of the antibiotic, azithromycin.

The Lihir Island campaign was initially successful, dramatically reducing the incidence of the disease. However, after two years, cases re-emerged. Molecular testing showed the bacteria were of a single type, however it was unclear if the re-emergence had a single source, or several. Additionally, a small proportion of the bacteria were found to be resistant to azithromycin, the first time any such resistance had been seen.

They found that, rather than re-emergence being due to a single source, missed case, or reintroduction, the re-emergence of cases after MDA was actually caused by at least three distinct types of the TPP bacteria – likely due to latent infections in asymptomatic individuals who didn’t receive treatment. By studying their genetic information, the researchers were able to map the evolution of the bacteria, with the aim to further understand its re-emergence following the MDA and inform future strategies.

Professor Nick Thomson, from Wellcome Sanger Institute and LSHTM, senior author of the paper and whose group pioneered whole genome sequencing techniques for Yaws, said: “The resolution afforded by genome sequencing to track agents of infectious diseases is vital for our efforts to control and, eventually, to eliminate them. It can help us understand how and where bacteria or other pathogens are spreading between people, as well as how they respond genetically to our attempts to control them. Hence, monitoring for drug resistance is also essential to defeat these diseases. The information can help target interventions and treatments so they have the most effect.”

Dr Michael Marks, from LSHTM, senior author of the paper, and a technical advisor for the World Health Organization (WHO) to the Yaws eradication campaign, said: "Yaws is one of many neglected tropical diseases, which combined affect around one billion people - usually in low- and middle-income countries. They are often diseases of poverty, affecting rural communities without access to sanitation and basic healthcare. WHO has laid out a new roadmap for the control, elimination and, in the case of yaws, eradicating these conditions over the coming decade."

Dr Marks says there is need for better near-patient diagnostics, and is currently working on a project aiming to assess the real-life accuracy of a new diagnostic test, the LAMP (loop-mediated isothermal amplification) test, in yaws-endemic areas of Ghana, Côte d’Ivoire and Cameroon.

One of the bacteria lines became resistant to azithromycin during the study, which the researchers went on to study using epidemiological data about the movement and interactions of people in the region. They found that azithromycin resistance can evolve and spread rapidly in TPP bacteria, and recommend careful monitoring following an MDA to enable the rapid detection of azithromycin resistance that could compromise MDA campaigns.

Dr Mathew Beale, first author of the study from the Wellcome Sanger Institute, said: “Even though an impressive 83% of the population were reached with antibiotic treatment initially, there were several instances of re-emergence of the bacteria. The development of antibiotic resistance is worrying, but the fact that it only occurred once after a mass drug administration is positive news. We still need to be very concerned about resistance, but it may be possible to manage it. Our results have big implications for how yaws elimination campaigns are run – we can recommend high treatment coverage initially and there needs to be careful surveillance and follow up to detect and swiftly treat any re-emergence, to prevent the bacteria spreading.”

The team also suggest considering alternative treatments for cases detected post-MDA, particularly where diagnostic testing for resistance is unavailable, since resistance is subsequently more likely to be present in the bacterial population.

Dr Oriol Mitjà, senior author of the paper at Lihir Medical Center, Papua New Guinea and the Fight Aids and Infections Disease Foundation, said: “While yaws doesn’t kill, it causes significant disease in thousands of children around the world. Yet it is easily treatable. Following up on treatment trials is vital – we need to know where and why the bacteria are re-emerging. The results from this study are influencing the next steps and approaches we take to eradicate this disease.”

Publication

Mathew Beale, et al. Yaws re-emergence and bacterial drug resistance selection after mass administration of azithromycin: a genomic epidemiology investigation. Lancet Microbe. DIO: 10.1016/S2666-5247(20)30113-0