A historic spike in diphtheria cases among migrants reveals gaps in Europe’s public health defenses and underscores why swift vaccination, real-time surveillance, and preparedness remain crucial to prevent the next crisis.
Study: Corynebacterium diphtheriae Outbreak in Migrant Populations in Europe. Image Credit: Kateryna Kon / Shutterstock.com
A recent study published in the New England Journal of Medicine discusses an alarming surge in diphtheria cases across multiple European countries that has raised global health concerns about regional transmission dynamics and insufficient vaccine coverage.
What is diphtheria?
Diphtheria is a highly transmissible and potentially life-threatening disease caused by infection with toxigenic strains of Corynebacterium diphtheriae that express the diphtheria toxin. This exotoxin inhibits eukaryotic protein synthesis.
While respiratory diphtheria is the classical presentation, cutaneous diphtheria, characterized by skin ulcers, also plays a major role in transmission, particularly in outbreak settings. Non-vaccinated children five years and younger are particularly vulnerable to diphtheria, with an estimated case fatality rate of 29% in non-vaccinated populations with untreated respiratory diphtheria.
Between 2016 and 2021, an average of 27 C. diphtheriae infection cases were recorded annually in the European Economic Area and the European Union. Nevertheless, diphtheria can become or remain endemic in regions with suboptimal vaccine coverage. Diagnosed cases in Europe are often detected among travelers and migrants from such regions.
In Europe, diphtheria cases are often detected in migrants and travelers from endemic regions. However, an unusual increase in C. diphtheriae infections was observed in several European countries in 2022.
About the study
In the present study, researchers from a pan-European consortium investigate the geographic and temporal dynamics of the diphtheria outbreak in 10 European countries in 2022. Diphtheria cases were retrospectively included based on isolates cultured between January and November 2022.
Only toxigenic isolates carrying the tox gene, confirmed by polymerase chain reaction (PCR) testing and whole-genome sequencing, were included in accordance with World Health Organization (WHO) recommendations for managing diphtheria outbreaks.
Toxin production was confirmed using Elek’s test. Clinical data were obtained from patient records, and interviews were conducted to collect information on the country of origin, arrival in the country, and transit countries.
C. diphtheriae isolates harboring the tox gene, as determined by polymerase chain reaction (PCR) testing, were considered for the analysis. Thereafter, all bacterial isolates underwent whole-genome sequencing and multi-locus sequence typing (MLST).
Sublineages (SLs) and genetic clusters were defined as groups of core-genome MLST profiles with a threshold of 500 and 25 allelic mismatches, respectively. A single-nucleotide polymorphism (SNP) analysis was also performed within four major genetic clusters.
Antimicrobial-susceptibility testing was performed for erythromycin and penicillin. Antimicrobial resistance genes and integrons were analyzed based on whole-genome sequences.
Clinical, genomic, and microbiological features of the outbreak
A total of 20 diphtheria cases were detected between January and July 2022. Soon thereafter, a marked surge in case numbers was observed, with 38, 74, 115, and 116 cases reported in subsequent months. A greater proportion of toxigenic C. diphtheriae infections were reported in 2022 than in previous years, as 363 isolates with the tox gene were identified among 362 patients.
About 98% of patients were male, whereas 96% reported recent migration. The median age was 18 years, with nearly half of all cases in those aged 16–20. Most patients originated from Afghanistan or Syria (83.5% of cases with a known country of origin), and the majority had migrated through the Western Balkans.
MLST revealed 16 STs, with 91% of isolates belonging to three unrelated STs of ST574, ST377, or ST384.
Cutaneous diphtheria predominated in this outbreak, with 268 patients (78%) presenting with skin ulcers. Respiratory diphtheria was identified in 53 cases (15%), and nine patients had both cutaneous and respiratory symptoms. Clinical symptoms were not associated with specific STs. Ten patients were not vaccinated, and four patients were vaccinated, whereas the vaccination status was unknown for the remaining 290 individuals.
The most frequently prescribed antibiotics were azithromycin, amoxicillin, clarithromycin, penicillin, doxycycline, and clindamycin. All hospitalized patients with respiratory diphtheria (n=12) were treated with both antibiotics and diphtheria antitoxin, with earlier administration associated with better outcomes. The only fatality occurred in a patient who experienced delayed antitoxin administration.
Streptococcus pyogenes, methicillin-resistant Staphylococcus aureus, and arcanobacteria were most commonly present during coinfections, with cutaneous diphtheria cases more likely to be affected by a coinfection. Seventeen patients were hospitalized, including 12 with respiratory diphtheria and five with cutaneous diphtheria.
Nineteen countries of origin and 28 transit countries were identified, with 83.5% of patients originating from Afghanistan or Syria. Almost all tested isolates were susceptible to penicillin, whereas 93.6% of tested isolates were sensitive to erythromycin treatment. All tested isolates were susceptible to amoxicillin.
One isolate was resistant to meropenem and penicillin, whereas 18 erythromycin-resistant isolates were resistant to tetracycline, ciprofloxacin, trimethoprim-sulfamethoxazole, and doxycycline.
Concurrent resistance to macrolides and beta-lactams was not observed for any isolate. Moreover, 81%, 33%, and 22% of tested isolates were resistant to trimethoprim-sulfamethoxazole, tetracycline, and ciprofloxacin, respectively.
A total of 12 SLs were identified, with SL384, SL574, and SL377 most frequently observed. Four major genetic clusters, designated as GC1, GC2, GC3, and GC9, were identified within these three SLs. A subset of isolates carried the ermX gene, which encodes erythromycin resistance, as well as blaOXA-2 and pbp2m genes that encode beta-lactam resistance.
The outbreak was multiclonal, involving several independent genetic lineages, and cross-border transmission was documented, with multiple clusters circulating in several countries. Genomic data indicated the circulation of the four main genetic clusters previously identified in 2022, which were also present in samples isolated one year later, suggesting sustained transmission.
Conclusions
The recent diphtheria outbreak was the largest surge in cases throughout Western Europe for the past seventy years. Nevertheless, infections primarily affected displaced populations entering Europe, with no secondary infections reported in resident populations during 2022 and only a small number (seven) identified in vulnerable non-migrant groups in 2023, including people experiencing homelessness and people who inject drugs.
The study findings warrant action to reduce the risk of future outbreaks, including greater awareness, vaccination, clinical surveillance of at-risk populations, and rapid diagnosis and screening. Increasing diphtheria antitoxin production and maintaining stockpiles for rapid deployment should also be prioritized. The authors further emphasize the importance of genomic surveillance, robust vaccination strategies (including boosters for adults to address waning immunity), and international data sharing to inform rapid public health responses.