Diphtheria is a severe infection caused in humans by toxigenic strains of Corynebacterium diphtheriae bacteria. If left untreated, it leads to death in 5 to 25% of cases. It generally affects the upper respiratory tracts, causing pseudomembrane formation and sometimes leading to suffocation. The infection can be complicated by systemic symptoms caused by the diphtheria toxin. Scientists from the Institut Pasteur joined forces with Yemeni doctors and scientists to shed light on the current outbreak in Yemen.
Diphtheria was the most deadly disease among children during the pre-vaccine era. Even though widespread vaccination has made the disease rare, outbreaks of diphtheria still occur in certain countries or situations where the public health system is in crisis. In Yemen, where civil war is raging, a major diphtheria outbreak has been ongoing since October 2017.
An epidemiology study thanks to an international collaborative effort
Scientists from the Institut Pasteur sought to investigate the epidemiological, clinical and microbiological features of this outbreak. "Our study is based on several national-level data sources and an international collaborative effort involving epidemiologists, microbiologists and experts in bacterial genomics. We defined the dynamics of the diphtheria epidemic and identified three outbreak periods in Yemen," explains Sylvain Brisse, Head of the Biodiversity and Epidemiology of Bacterial Pathogens Unit. The Yemen outbreak has affected almost all governorates (provinces), with 5,701 probable cases and 330 deaths during the period from October 2017 to April 2020. Scientists observed that the proportion of cases among children aged 0 to 4 fell during the second period (June 2018 to May 2019) following a vaccination campaign conducted to control the outbreak. According to Noémie Lefrancq, who contributed to the study, "This data suggests that although the vaccination campaign did not stop transmission of the disease, it helped to protect young children during subsequent outbreak periods".
The various sublineages identified point to regional transmission
During the study, clinical isolates (strains of Corynebacterium diphtheriae) were also characterized microbiologically. Various microbiological culture, genomic sequencing, antimicrobial susceptibility and diphtheria toxin production tests were conducted, providing valuable data on the nature of the infectious strains. Almost all of the outbreak isolates produced the diphtheria toxin. "We identified six distinct phylogenetic sublineages of Corynebacterium diphtheriae, four of which are genetically related to isolates from Saudi Arabia, Eritrea and Somalia, which suggests regional transmission dynamics", continues Sylvain Brisse. Inter-sublineage genomic variations in genes associated with antimicrobial resistance, iron acquisition and adhesion to host cells were observed. The predominant sublineage (70% of isolates) is resistant to trimethoprim and associated with unique genomic features, more frequent neck swelling (a classic diphtheria symptom) and a younger age of patients. Its most recent common ancestor was placed in 2015, which indicates silent circulation of C. diphtheriae in Yemen long before the outbreak was officially detected.
The combined epidemiological, clinical and microbiological data analyzed during this study show that catch-up vaccination appears to have effectively protected some of the targeted population (children aged 0–4 years). This study also demonstrated that multiple strains of C. diphtheriae may emerge during a diphtheria outbreak. A fall in vaccination rates encourages the clinical expression and the simultaneous spread of the strains which previously circulated asymptomatically among the vaccinated populations. The phenotypic heterogeneity of the circulating strains, with different antibiotic sensitivity profiles, for example, highlights the need to scale up laboratory test capacity and real-time microbiological monitoring during diphtheria outbreaks. A rapid response – in this case thanks to a partnership with the French National Reference Center at the Institut Pasteur – helps to provide critical information to treat clinical cases, implement the vaccine strategy and control the spread of diphtheria.
This study is part of the Vaccinology and Immunotherapy Initiative of the Institut Pasteur's strategic plan for 2019-2023.
Ongoing diphtheria outbreak in Yemen: Epidemiological, clinical and genomic insights, The Lancet Microbe, 26 may 2021
Edgar Badell1,2, Abdulilah Alharazi3, Alexis Criscuolo4, The NCPHL diphtheria outbreak working group#, Khaled Abdullah Ali Almoayed13, Noémie Lefrancq5, Valerie Bouchez1, Julien Guglielmini4, Melanie Hennart1,6, Annick Carmi-Leroy1,2, Nora Zidane1, Marine Pascal-Perrigault1, Manon Lebreton1, Helena Martini7, Henrik Salje5,8, Julie Toubiana1,2,9, Fekri Dureab10,11, Ghulam Dhabaan12,* and Sylvain Brisse1,2,*
#The NCPHL diphtheria outbreak working group: Abdulaziz A. Rawah, Mohammed A. Aldawla, kram M. Al-Awdi, Nabila M. Al-Moalmy, Huda Z. Al-Shami, Ali A. Al-Somainy
1 Institut Pasteur, Biodiversity and Epidemiology of Bacterial Pathogens, Paris, France
2 Institut Pasteur, National Reference Center for Corynebacteria of the diphtheriae complex, Paris, F-75724, France
3 National Centre of the Public Health Laboratories (NCPHL), Sana'a, Yemen
4 Hub de Bioinformatique et Biostatistique ‒ Département Biologie Computationnelle, Institut Pasteur, Paris, France
5 Mathematical Modelling of Infectious Diseases Unit, Institut Pasteur, UMR2000, CNRS, Paris, France
6 Sorbonne Université, Collège doctoral, Paris, France
7 Department of Microbiology, National Reference Centre for toxigenic corynebacteria, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel (VUB), Laarbeeklaan 101, Brussels, Belgium
8 Department of Genetics, University of Cambridge, Cambridge, UK
9 Université de Paris, General Paediatrics and Paediatric Infectious Diseases Department, Hôpital Necker-Enfants malades, APHP, Paris, France
10 Institute for Research in International Assistance, Akkon Hochschule, Berlin, Germany
11 Heidelberg Institute of Global Health, Heidelberg, Germany
12 Mount Sinai Hospital, University Health Network, University of Toronto, Toronto, Canada
13 Department of Diseases Control and Surveillance, Ministry of Public Health and Population, Sana'a, Yemen
This study is part of the priority scientific area Emerging infectious diseases of the Institut Pasteur's strategic plan for 2019-2023.