Yaws: Neglected tropical disease is re-emerging

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(A) Nodule with yellow crust on the right leg of a patient with primary yaws. (B) Photomicrograph of skin biopsy showing yaws lesions. Spirochete organisms are stained bright red by the Treponema pallidum immunohistochemical stain (× 400 magnification). (C) Loss of clarity of the cortex of the distal radius and ulna and organized periosteal reaction. (D) Resolution of bone lesions at 4 weeks after azithromycin treatment.

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.

The re-emergence followed a mass drug administration (MDA) campaign that aimed to eliminate the disease in Papua New Guinea.

Researchers at the Wellcome Sanger Institute, the London School of Hygiene & Tropical Medicine, the Fight Aids and Infections Disease Foundation, Spain, the University of Washington and the University of Papua New Guinea, report their findings today in Lancet Microbe. The results will influence the global elimination strategy for this disease.

Yaws, caused by the bacterium Treponema pallidum subspecies pertenue (TPP), can cause 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 yaws using Mass Drug Administration (MDA) of the antibiotic, azithromycin.

An MDA campaign on Lihir Island, Papua New Guinea, in 2013 reached 83 percent of the population (15-18,000 people) and was initially successful, dramatically reducing the incidence of the disease.

But after two years, cases of the disease starting increasing. Molecular testing showed the bacteria were of a single type, however it was unclear if the re-emergence had a single source, or several. In addition, a small proportion of the bacteria were found to be resistant to azithromycin, the first time any such resistance had been seen.

In this new study, Sanger researchers sequenced the genomes of bacteria from 20 swab samples taken during the follow up of the MDA campaign in Lihir. The aim was to further understand the re-emergence following the MDA and inform future strategies.

Comparing the DNA sequences of the TPP bacteria, the team constructed phylogenetic ‘family’ trees to map their evolution. DNA sequences change over time at a constant rate as organisms evolve, and so it is possible to determine the relatedness of individual samples and relate that back to the patient and possible routes of infection.

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 TPP lineages. The most likely explanation for this is that these were caused by latent infections in people, without symptoms, who didn’t receive the treatment.

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.

Of the three lineages linked to the re-emergence, one became resistant to azithromycin during the study. To study this antibiotic resistance, the team combined the genomic data with epidemiological data about the movement and interactions of people in the region.

This showed that resistance to azithromycin can evolve and spread rapidly in TPP. The authors recommend careful monitoring following an MDA to enable the rapid detection of azithromycin resistance that could compromise MDA campaigns. They 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. Mathew Beale, first author of the study from the Wellcome Sanger Institute, said: “Even though an impressive 83 percent 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.”

Dr. Michael Marks, senior author of the paper at London School of Hygiene & Tropical Medicine, 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. 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.”

Professor Nicholas Thomson, senior author of the paper based at the Wellcome Sanger Institute and the London School of Hygiene & Tropical Medicine, 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.”


The framework of neglected tropical diseases (NTDs) began in the early 2000s after a group of “other diseases”, highlighted within Millennium Development Goal 6, was rebranded based on a set of common features.

The original NTDs were all chronic and debilitating infections, most of which were also parasitic diseases, with the added component that they mostly occurred among the extreme poor.

In 2005, an initial list of 13 conditions was published in PLOS Medicine, two years before PLOS Neglected Tropical Diseases began, focused exclusively on the major NTDs of sub-Saharan Africa (Box 1) [1].

Box 1. Original list of 13 African Neglected Tropical Diseases and Their Major Etiologic Agents published in PLOS Medicine in 2005*

Protozoan Infections

African trypanosomiasis                    Trypanosoma gambiense and Trhodesiense

Visceral leishmaniasis (Kala-azar)                Leishmania donovani

Helminth Infections

Soil-transmitted helminth infections

Ascariasis                                                           Ascaris lumbricoides

Trichuriasis                                                      Trichuris trichiura

Hookworm infection               Necator americanus

Schistosomiasis

Urinary schistosomiasis                     Schistosoma haematobium

Hepatobiliary schistosomiasis             Schistosoma mansoni

Lymphatic filariasis                            Wuchereria bancrofti

Onchocerciasis                                   Onchocerca volvulus

Dracunculiasis                                    Dracunculus medinensis

Bacterial Infections

Trachoma                                          Chlamydia trachomitis

Leprosy                                             Mycobacterium leprae

Buruli ulcer                                         Mycobacterium ulcerans

* Adapted from [1]

Later, the WHO expanded the 2005 list to include conditions they considered to be of global public health importance (Table 1). Among the helminth infections, they added echinococcosis, foodborne trematodiases, and taeniasis/cysticercosis. Chagas disease was added to the list of protozoan infections, while yaws (endemic treponematoses) was added to bacterial infections. A group of fungal deep mycoses was also added.

Viral infections were not on the original list, but the WHO added two arbovirus infections–dengue and chikungunya, as well as rabies. They also added scabies and other ectoparasites, in addition to snakebite envenomation [2].

Table 1

Listing the world’s NTDs by WHO and PLOS Neglected Tropical Diseases.

NTDs on the cusp refer to conditions that might be added downstream.

Classes of NTDsNTDs recognized by WHO [2]NTDs recognized by PLOS Neglected Tropical Diseases [3]NTDs on the cusp
Helminth infections (and their vectors)– Dracunculiasis
– Echinoccocosis
– Foodborne Trematodiases
– Lymphatic filariasis
– Onchocerciasis
– Schistosomiasis
– Soil-transmitted helminthiases (Ascariasis, Hookworm Diseases, Trichuriasis, Strongyloidiasis)
– Taeniaisis/Cysticercosis
All human helminth infections including but not restricted to:
– Dracunculiasis
– Echinococcosis
– Foodborne Trematodiases
– Loiasis
– Lymphatic Filariasis
– Onchocerciasis
– Other food-borne helminthiases,
including Trichinosis,
Anisakiasis, Gnathostomiasis,
etc.
– Schistosomiasis
– Soil-transmitted helminthiases (Ascariasis, Hookworm Diseases, Trichuriasis, Strongyloidiasis)
– Taeniasis-Cysticercosis
– Toxocariasis and other larva migrans, e.g. Baylisascaris
– None (all human helminth infections are currently considered)
Protozoan infections
(and their vectors)
– Chagas disease
– Human African trypanosomiasis
– Leishmaniasis
– Amebiasis including Naegleria
– Babesiosis
– Balantidiasis
– Chagas Disease
– Giardiasis
– Human African
Trypanosomiasis
– Leishmaniasis
– Plasmodium vivax and other non-Pfalciparum malarias
– Blastocystiasis*
– Cryptosporidiosis and
cyclosporiasis
– Toxoplasmosis
Bacterial infections (and their vectors)– Buruli ulcer
– Leprosy (Hansen’s disease)
– Trachoma
– Yaws (Endemic treponematoses)
– Bartonella
– Bovine Tuberculosis in Humans
– Buruli Ulcer
– Cholera
– Enteric pathogens (Shigella, Salmonella, Ecoli)
– Leprosy
– Leptospirosis
– Melioidosis
– Relapsing Fever
– Trachoma
– Yaws and other tropical treponematoses (Bejel, Pinta)
– Q fever
– Group A Streptococcal disease
Fungal infections– Mycetoma, chromoblastomycosis, and other deep mycoses– Mycetoma, chromoblastomycosis, and other deep mycoses
– Paracoccidiomycosis
– Cryptococcosis
– Histoplasmosis
Viral infections (and their vectors)-Dengue and Chikungunya
-Rabies
– Arboviral infections including Dengue, Chikungunya, Zika, Japanese encephalitis, Jungle yellow fever and others
– Enterovirus 71 and related viruses
– HTLV-1, HTLV-2 and other non-HIV retrovirus infections
– Rabies
– Rift Valley fever
– Viral hemorrhagic fevers
– Henipavirus species e.g. Nipah virus
Ectoparasitic infestations– Scabies and other ectoparasites– Scabies, Myiasis, and other ectoparasites– None
Non-infectious diseases or conditions– Snakebite envenoming– Podoconiosis
– Snakebite envenoming
– Sickle-cell Anemia
* The taxonomic position of the stramenopile-like, unicellular protist Blastocystis remains uncertain.

An expanded NTD list for PLOS Neglected Tropical Diseases

At PLOS Neglected Tropical Diseases, the editors highly support the WHO list but also recognize that the community of NTD investigators conduct research and public health efforts on an expanded group of conditions that still qualify as NTDs due to evidence that they constitute chronic and debilitating conditions disproportionately affecting populations living in extreme poverty [3]. Table 1 lists the NTDs currently recognized by PLOS Neglected Tropical Diseases compared to those recognized by the WHO.

Among the helminth infections, PLOS Neglected Tropical Diseases largely considers just about any helminthic disease of humans. In some cases, we even consider important veterinary helminthiases if they are linked to human zoonotic disease.

In our scope, we specifically mention some important conditions that are not included in the WHO list, including loiasis, strongyloidiasis, and toxocariasis (and other larva migrans syndromes), which represent prevalent, high disease burden, human illnesses.

For protozoan infections, we include some key intestinal infections including amebiasis, babesiosis, giardiasis, and others. PLOS Neglected Tropical Diseases, along with the WHO and some other international agencies, does not consider Plasmodium falciparum malaria to be an NTD.

Nevertheless, PLOS Neglected Tropical Diseases recognizes that P. vivax and other non-P. falciparum malarias – classically non-fatal but debilitating tropical infections–are understudied relative to falciparum malaria. Therefore, we consider and publish papers on non-falciparum malaria.

For bacterial diseases, the PLOS Neglected Tropical Diseases list is notable for adding cholera and other enteric diarrheal pathogens not considered as NTDs by the WHO, in addition to bartonellosis, bovine tuberculosis, leptospirosis, melioidosis, relapsing fever and Q fever, each an important disease in resource-poor regions.

While we consider yaws and other tropical treponematoses as NTDs, we are not ordinarily reviewing or publishing syphilis papers unless there are unusual or specific circumstances to justify this.

For viral infections, we consider just about all arbovirus infections if they affect low- and middle-income countries, in addition to Ebola and other viral hemorrhagic fevers, as well as rabies. We now also consider enterovirus 71 or some of the enterovirus infections, as well as HTLV-1 and HTLV-2 infections, if they specially relate to resource-poor countries.

Both the WHO and PLOS Neglected Tropical Diseases lists include ectoparasitic infestations, especially scabies. We also consider two non-infectious conditions–podoconiosis and snakebite envenoming.

Beyond these NTDs, PLOS Neglected Tropical Diseases also considers the important nutritional links underlying NTDs, and co-infections between NTDs and HIV/AIDS, malaria, and tuberculosis. We are also enthusiastic about publishing on the social sciences or public policy if these aspects pertain to neglected diseases.

Other infections “NTDs on the cusp”

We also wish to highlight here some of our more thought-provoking, interesting, and polemical ongoing discussions regarding specific conditions and diseases, especially some that are most debated in terms of whether they truly represent NTDs.

Factoring into deliberations and decisions on whether to include a specific disease or condition within the scope of PLOS Neglected Tropical Diseases is the availability of disease burden estimates for that specific condition, and if that burden occurs in resource-poor settings.

Delays in accepting submissions in some topics may reflect a lack of editorial expertise to appropriately review and handle such papers, but we will strive to acquire that expertise in order to serve the needs of our community.

Regarding protozoan infections, emerging evidence from the Global Enteric Multicenter Study (GEMS) clearly implicates cryptosporidiosis as an important NTD, especially of young children.

Therefore, PLOS Neglected Tropical Diseases will add this disease to our list [4]. However, the journal is less interested in cryptosporidiosis outbreaks in North America and Europe due to direct water contamination unrelated to poverty. Similarly, toxoplasmosis is traditionally considered a disease of North America and Europe, but an evidence base is building for high rates of disease transmission in Africa and Latin America.

For that reason, toxoplasmosis as it pertains to low-resource countries would be considered relevant. Blastocystiasis is a disease caused by an organism with an unusual phylogeny, and there is controversy whether it constitutes an actual pathogen. However, we have an interest in these discussions and are willing to consider papers on this topic.

For bacterial infections, we currently consider those diseases that disproportionately affect impoverished populations. Relative to the WHO list, adding relapsing fever, leptospirosis, bartonellosis, cholera, and melioidosis to the PLOS Neglected Tropical Diseases list was a relatively straightforward decision because of their global public health impact.

However, adding Salmonella, Shigella, and other enteric bacterial infections occurred with the understanding that we would focus on topical papers relevant to the disease-endemic countries of poverty. We now receive occasional correspondence regarding group A streptococcus and its importance in the pathogenesis of rheumatic fever, glomerulonephritis, and other conditions of the tropics.

Given that scabies is a major predisposing factor to streptococcal infections and disease sequelae, increasingly we are willing to consider papers on this topic. Deep fungal infections are now a prominent component of the PLOS Neglected Tropical Diseases papers. We are also willing to consider papers on cryptococcosis and histoplasmosis if they specifically pertain to disease in the setting of extreme poverty.

For viral infections, the scope of PLOS Neglected Tropical Diseases is already larger relative to the WHO list, especially for arboviral infections. We agree that some zoonotic viruses, such as henipaviruses that include Nipah and Hendra viruses, represent emerging tropical disease pathogens, and we are working to expand our editorial expertise to handle and review these papers. At present, we are willing to consider papers on these topics on a case-by-case basis.

Finally, we recognize that sickle cell anemia in many respects resembles an NTD in its clinical and epidemiologic features. We have published a thoughtful editorial making the case why sickle cell anemia might be considered as an NTD [5]. At this time, however, there are already several eminent hematology journals better equipped to review papers on this topic.

Ultimately, the editors at PLOS Neglected Tropical Diseases are open to new ideas and articles about diseases not on the current list. Please note that NTDs are not rare diseases, and therefore rare diseases are beyond the scope of this journal.

Final comment

PLOS Neglected Tropical Diseases is a community journal, and in that context, it is important for the editors to be responsive to the NTD scientific community regarding our current and future scope.

We very much look forward to hearing from you about our current topics and expertise, and whether there are new directions we should consider. As such, we encourage prospective authors to send us a viewpoint or propose an editorial article to make a case that an additional disease, illness, or condition qualifies as an NTD.

These articles are generally well received, are impactful and can serve to drive the field forward. In this spirit, we would also like to emphasize that PLOS Neglected Tropical Diseases focuses on human disease, not infections that only afflict livestock and other animals unless these diseases also impact human health and represent a public health problem.

Further, we would like to reiterate that the focus of our journal is on translational or epidemiological studies, and less so on pure, basic molecular research not associated to improvement of human health.

The scope of PLOS Neglected Tropical Diseases will always be dynamic. We plan to revisit the scope of the journal every five years or so. Once the editorial board arrives at a consensus that an infection or condition qualifies as an NTD, we will strive to bring onboard new expertise to ensure that all NTDs find a home at PLOS Neglected Tropical Diseases.

References

1. Molyneux DH, Hotez PJ, Fenwick A (2005) “Rapid-Impact Interventions”: How a Policy of Integrated Control for Africa’s Neglected Tropical Diseases Could Benefit the Poor. PLoS Med 2(11): e336 10.1371/journal.pmed.0020336 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

2. World Health Organization https://www.who.int/neglected_diseases/diseases/en/, accessed September 2, 2019.

3. PLOS Neglected Tropical Diseases https://journals.plos.org/plosntds/s/journal-information, accessed September 2, 2019.

4. Delahoy MJ, Omore R, Ayers TL, Schilling KA, Blackstock AJ, Ochieng JB, et al. (2018) Clinical, environmental, and behavioral characteristics associated with Cryptosporidium infection among children with moderate-to-severe diarrhea in rural western Kenya, 2008–2012: The Global Enteric Multicenter Study (GEMS). PLoS Negl Trop Dis 12(7): e0006640 10.1371/journal.pntd.0006640 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

5. Ware RE (2013) Is Sickle Cell Anemia a Neglected Tropical Disease? PLoS Negl Trop Dis 7(5): e2120 10.1371/journal.pntd.0002120 [PMC free article] [PubMed] [CrossRef] [Google Scholar]


More information: Mathew A Beale et al, Yaws re-emergence and bacterial drug resistance selection after mass administration of azithromycin: a genomic epidemiology investigation, The Lancet Microbe (2020). DOI: 10.1016/S2666-5247(20)30113-0

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