Companion Animals and Diabetes Mellitus as Risk Factors for Diphtheria Due to Corynebacterium Ulcerans

Corynebacterium (C.) ulcerans is becoming increasingly important as a pathogen causing diphtheria in Germany. C. ulcerans is zoonotically transmitted to humans, especially by companion animals, and mostly causes cutaneous or wound diphtheria (1). The disease can be fatal. Since 2017, all diphtheria toxin-producing Corynebacteria have been notifiable—no longer just C. diphtheriae (2). In 2019–2022, the Robert Koch Institute (RKI) and the German National Consiliary Laboratory for Diphtheria jointly conducted enhanced diphtheria surveillance in order to, among others, identify potential risk factors for infections with C. ulcerans.

Methods

Local health authorities were invited to complete a questionnaire for diphtheria cases, which included, among others, data on the vaccination history, comorbidities, and animal contact. We used a univariable analysis to evaluate all 268 diphtheria cases in 2017–2022 that met the RKI’s reference case definition, and 111 (41.4%) accompanying questionnaires. An unmatched case–case analysis of 31 cases of C. ulcerans and 36 comparison cases of C. diphtheriae yielded odds ratios (OR) for potential risk factors.

Results

Diphtheria cases in 2017–2022

In 2017–2022, 268 diphtheria cases that met the reference definition were reported to the RKI. These included 146 cases among migrants who had newly arrived in Germany and were part of a Europe-wide outbreak of imported diphtheria from the summer of 2022 (3). Of the remaining 122 cases, 88 (72.1%) were infected with C. ulcerans and 34 (27.9%) with C. diphtheriae; 89 (73.0%) infections had been acquired within Germany (autochthonously), 15 (12.3%) were travel-associated, 14 (11.5%) were associated with migration, and in 4 (3.3%) the location of the exposure was not known. In relation to all 268 cases, the persons infected with C. ulcerans were older than those with C. diphtheriae (median 69 versus 20 years; p<0.001). Cutaneous diphtheria affected 79 (89.8%) of C. ulcerans cases and 159 (88.3%) of C. diphtheriae cases. Respiratory diphtheria was present in 4 (4.5%) of the cases with C. ulcerans and 11 (6.1%) of those with C. diphtheriae. Double manifestation (for example, cutaneous diphtheria with colonization of the pharynx) was present in 15 (5.6%) cases. The vaccination status was known for 128 (47.8%) persons; 86 had ever been vaccinated; 37 of these had at least once been vaccinated in a timely manner, i.e. before the start of the incubation period. All cases were confirmed clinically and by laboratory testing. All federal states had reported cases.

Risk factors for infections with C. ulcerans

In all 31 (100%) cases of C. ulcerans, the infection had been acquired autochthonously. Among the 36 comparison cases of C. diphtheriae, 1 case (2.8%) was autochthonous, 3 (8.3%) had been infected during travel (Egypt, the Gambia, Myanmar), and 32 (88.9%) along the migration route. 20 (64.5%) persons with C. ulcerans infection and 3 (8.3%) with C. diphtheriae reported animal contact (Table). Therefore, in persons with C. ulcerans the likelihood of owning companion animals was 20 times that of persons with C. diphtheriae (OR: 20.00; 95% confidence interval [4.97; 80.47]; p<0.001). Cats and dogs were reported most commonly.

Table. Odds ratio of exposure for the association between individual possible risk factors and other variables with C. ulcarans infection (cases) versus C. diphtheriae infection (comparison cases), calculated using univariable analysis.

		Cases		Odds of exposure		OR of exposure [95% CI]*3
		C. ulc.	C. diph.	C. ulc.	C. diph.
Potential risk factors
Companion animal ownership	Yes No	20 11	3 33	1.82	0.09	20.00*** [4.97; 80.47]
Dog ownership	Yes No	13 6	2 1	2.17	2.00	1.08 0.08; 14.41]
Cat ownership	Yes No	13 5	2 1	2.60	2.00	1.30 0.10; 17.73]
Diabetes mellitus	Yes No	16 15	2 34	1.07	0.06	18.13*** 3.70; 88.97]
DFS*1	Yes No	11 15	1 34	0.73	0.03	24.93*** 2.95; 210.94]
Further variables of interest
Comorbidity	Yes No	18 11	3 31	1.64	0.10	16.91*** 4.16; 68.74]
Sex*2	F M	10 21	1 35	0.48	0.03	16.67** 1.99; 139.64]
Leg ulcer	Yes No	5 26	1 35	0.19	0.03	6.73 0.74; 61.12]
Wound	Yes No	25 6	27 9	4.17	3.00	1.39 [0.43; 4.46]
Age in years		-	-	-	-	1.10*** 1.07; 1.15]
Migration	Yes No	0 31	32 4	0.00	8.00	0.00*** -
Occupational contact with animals	Yes No	3 27	0 31	0.11	0.00	-
Raw milk products	Yes No	2 22	0 7	0.09	0.00	-

For age, odds and odds ratios per life year are shown. Missing observations for 31 cases of C. ulcerans (C. ulc.) and 36 comparison cases of C. diphtheriae (C. diph.): no data available. Multiple answers possible.

^*1DFS, diabetic foot syndrome;

^*2F, female; M, male;

^*395% CI, 95% confidence interval;

^**, p<0.01;

^***, p<0.001

Comorbidities were mentioned in 18 (58.1%) cases of C. ulcerans and 3 (8.3%) comparison cases. The most commonly named was diabetes mellitus; in individual cases, cardiovascular disorders, hypertension, prostate cancer, and hypothyroidism were named. 11 (35.5%) cases with C. ulcerans and 1 (2.8%) comparison case had diabetic foot syndrome. The combination of companion animal contact and diabetes mellitus applied to 9 (29.0%) cases with C. ulcerans and 1 (2.8%) comparison case.

Discussion

This first analysis of the epidemiology of C. ulcerans in Germany since the expansion of mandatory notification requirements shows an association between companion animals, diabetes mellitus, and diphtheria caused by C. ulcerans. This pathogen has replaced C. diphtheriae as the most common pathogen causing diphtheria acquired within Germany in the study period. 65% of persons who had diphtheria caused by C. ulcerans reported owning companion animals—notably more than those 44% of households in Germany that kept companion animals in 2022 (4). Older people are likely to have a greater probability to become infected with C. ulcerans as a result of contact with companion animals as they tend to be more commonly affected by comorbidities and by chronic wounds due to diabetes mellitus, which Corynebacteria may colonize.

Indications of a double manifestation of cutaneous and respiratory diphtheria were seen in about 6% of cases of C. ulcerans and C. diphtheriae. For this reason, it is important to always consider both forms of manifestation in suspected diphtheria. Furthermore, genome sequencing of C. diphtheriae isolates since 2024 also indicates that persons with cutaneous diphtheria can transmit the pathogen in such a way that cases of respiratory diphtheria can occur (5).

Limitations

Limitations include the fact that the case–case analysis allows only conclusions about risk factors for diphtheria with C. ulcerans compared to diphtheria with C. diphtheriae, but not for diphtheria in general. Furthermore, cases and comparison cases differ in that the comparison cases are almost exclusively outbreak-associated and therefore younger, male, and had hardly any recorded comorbidities. For many cases the vaccination status was unknown.

Recommendations

In persons with diabetes mellitus, diabetic foot syndrome, or chronic wounds, medical professionals should consider cutaneous diphtheria early on and ask about ownership of companion animals or other contact with animals. Where infection is suspected, wound swabs and a deep pharyngeal swab should be taken, since the pharynx may be asymptomatically colonized. In case of a positive finding, companion animals should be examined and treated by a veterinarian if required. Primary laboratories should send Corynebacteria strains from human samples for comprehensive cost-free diagnostic testing to the German National Consiliary Laboratory for Diphtheria; this also applies, by arrangement, to animal samples. Vaccination is the most important protection against diphtheria. Therefore, medical and nursing staff should ensure that patients and themselves are fully vaccinated.