# The etiology of exudative cutaneous ulcers in a yaws-endemic community prior to receipt of antimicrobials is similar to that found in communities after mass treatment with azithromycin

## TL;DR

This study finds that the same bacteria cause skin ulcers in children in a yaws-endemic area, regardless of whether they received mass antibiotic treatment.

## Contribution

The study demonstrates that TPE, HD, and SP are primary causes of cutaneous ulcers in an untreated population, confirming findings from a previously treated area.

## Key findings

- TPE, HD, and SP DNAs were detected in 31.9%, 28.1%, and 25.4% of specimens respectively.
- Mixed infections with two or three pathogens occurred in 16.5% of cases.
- Idiopathic ulcers were found in 31.5% of specimens, with Arcanobacterium haemolyticum as the most abundant taxon.

## Abstract

Mass drug administration (MDA) of azithromycin (AZ) and case finding and treatment of children with cutaneous ulcers (CUs) have been trialed as strategies to eliminate yaws. Metagenomic sequencing of CU swabs obtained from children 3 to 4 years after the initiation of a yaws elimination campaign on Lihir Island showed enrichment for Treponema pallidum subsp. pertenue (TPE), Haemophilus ducreyi (HD), Streptococcus pyogenes (SP), and several anaerobic bacteria. Whether these results were influenced by AZ pressure or are generalizable to other populations is unknown. Here, we performed quantitative PCR (qPCR) for TPE, HD, and SP DNAs and metagenomic sequencing on 260 CU specimens collected from children on New Britain Island, whose inhabitants had not received MDA of AZ. Based on qPCR results, specimens were classified as containing no pathogens, a single pathogen, or multiple pathogens. 31.9% of the specimens contained SP, 28.1% HD, and 25.4% TPE DNAs; mixed infections with two or three pathogen DNAs occurred in 16.5% of cases. No pathogen DNA was detected in 31.5% of the specimens, which were defined as idiopathic ulcers (IUs). In most categories, the same pathogen(s) used to classify the ulcers by qPCR were the most abundant taxa present in the specimens. In IU, the most abundant taxon was Arcanobacterium haemolyticum; however, its relative abundance was similar across all groups, suggesting that this organism may adapt to the CU environment rather than represent a cause of IU. These data indicate that TPE, HD, and SP are the primary causes of CU in this untreated population.

Cutaneous ulcers (CUs) affect ~100,000 children annually in tropical regions. After mass drug administration (MDA) of azithromycin (AZ) failed to eradicate yaws, the World Health Organization proposed an integrated disease management strategy to control CU, which emphasizes identifying the causative pathogens in each population. This is critical because organisms associated with CU vary geographically, with Treponema pallidum subsp. pertenue (TPE), Haemophilus ducreyi (HD), Streptococcus pyogenes (SP), and Leishmania spp. predominating in different countries. We previously found that TPE, HD, and SP DNAs were enriched in CU specimens from children on Lihir Island in Papua New Guinea (PNG), a population heavily exposed to AZ. Here, we show that these three organisms were also the major pathogens in CU specimens from children on New Britain Island in PNG, whose population had not received MDA of AZ, suggesting that our previous findings are generalizable within PNG and not a consequence of AZ exposure.