When Travel Leaves a Mark: Blistering Feet in a Ten-year-old Boy After a Trip to the Sahel

CASE A 10-year-old boy presented to the emergency department in September 2024 because of slowly progressive blistering and uncomfortable lesions on his right foot (Fig. 1). The lesions started 10 days before presentation, after returning from a 2-week trip to Mali. During the trip, he visited friends and relatives in both urban and rural areas, including sleeping on a farm where ungulates were kept and running around barefoot during the rainy season. The boy’s medical history included infections such as varicella, impetigo, conjunctivitis and viral upper respiratory tract infections, none of which required hospitalization. He reported no ill contacts, and he was fully vaccinated according to the basic vaccination schedule recommended by the Belgian Superior Health Council.1FIGURE 1.: Clinical examination of blistering lesions on the dorsum of the right foot. Pictures were taken during clinical examination on days 1 (initial presentation at the emergency room), 5 and 8. Clinical examination revealed an afebrile, healthy looking child with multiple white-grayish blistering lesions on the dorsum of his right foot. Physical examination otherwise revealed no other abnormalities. Vital signs such as body temperature, respiratory rate and heart rate were within normal ranges for his age. The boy weighed 29 kg without evidence of recent weight loss or gain. At presentation, he reported a pain score of 3 on a scale of 0 (no pain) to 10 (worst pain imaginable). Diagnostic workup included wound swabs for Gram stain and culture, as well as Mpox polymerase chain reaction (PCR) was also included because of the recent outbreak in the Democratic Republic of Congo and its neighboring countries. No additional blood analysis or imaging studies were performed because symptoms were mild and localized to his right foot and in the absence of fever or systemic signs. With the possibility of an Mpox infection in mind, the patient was put in home isolation until the PCR result was known. Empiric antibiotic therapy was initiated with oral flucloxacillin together with topical application of iso-betadine. DENOUEMENT The Gram stain of the wound swab showed Gram-positive cocci suggestive of Streptococci and Staphylococci as well as Gram-positive rods (Fig. 2A). From the wound culture (Fig. 2B), methicillin-susceptible Staphylococcus aureus, Streptococcus pyogenes and surprisingly, Corynebacterium diphtheriae were isolated. Additionally, the result of the Mpox PCR came back negative.FIGURE 2.: Gram stain and aerobic culture of wound swabs taken at initial presentation to the emergency room. A: Gram stain showed Gram-positive rods and cocci (type Streptococci and Staphylococci). B: Aerobic wound culture on Columbia agar with 5% sheep blood. C: Pure subculture of Corynebacterium diphtheriae to examine toxin production. Antibiotic susceptibility testing was performed for C. diphtheriae using disk diffusion (penicillin G 1 µg, linezolid 10 µg, vancomycin 5 µg, tetracycline 30 µg, ciprofloxacin 5 µg and clindamycin 2 µg) and E-testing (erythromycin). The latter showed a minimum inhibitory concentration of erythromycin of 0.032 mg/L, well below the European Committee on Antimicrobial Susceptibility Testing breakpoint of 0.060 mg/L, confirming eligibility for treatment with a macrolide antibiotic. Furthermore, antibiotic susceptibility testing was performed for methicillin-susceptible S. aureus and S. pyogenes using the Vitek 2 (BioMérieux, Marcy l’Étoile, France), both also showing susceptibility to erythromycin. A pure culture of the C. diphtheriae strain was prepared (Fig. 2C) and sent to the Belgian reference laboratory of UZ Brussel for analysis of diphtheria toxin production. Real-time PCR showed that the diphtheria toxin gene (tox) was present, and toxin production was confirmed using an Elek immunoprecipitation test.2 The patient returned to the pediatric hospital on days 5 and 8 for re-evaluation (Fig. 1) and wound swabs were obtained for additional cultures, which eventually showed no growth of skin pathogens. Nasopharyngeal colonization with C. diphtheriae was assessed and a thorough skin examination was performed in both our patient and his close contacts. All were negative, indicating that the patient had to stay in contact but not droplet isolation and that the close contacts did not require antibiotic prophylaxis. Oral flucloxacillin was continued for 7 days, and erythromycin was added for a 14-day course. Our patient showed a favorable clinical response with progressive drying and healing of the blisters. Rapid contact tracing by the health facility’s infection prevention team timely identified 2 emergency room healthcare workers eligible for prophylactic treatment with azithromycin. Although respiratory diphtheria is rare these days, cutaneous diphtheria should be included in the broad differential diagnosis of skin lesions in travelers or migrants. Our patient presented with progressive blistering and painful lesions on his right foot. Wound culture revealed a polymicrobial infection and, most surprisingly, a case of cutaneous diphtheria. Co-infections with S. aureus and S. pyogenes in addition to C. diphtheriae are often reported in the literature. This stresses the need for thorough microbiologic investigations of ulcerative lesions to rule out diphtheria, even if other skin pathogens have been identified. Indeed, growth of C. diphtheriae can easily be overlooked in wound cultures on nonselective growth media containing skin commensals and other pathogens. Matrix-Assisted Laser Desorption/Ionization Time-Of-Flight Mass Spectrometry, however, can reliably identify C. diphtheriae. In Belgium, every C. diphtheriae isolate must be sent to the national reference center for analysis of toxin production.3 PCR of the toxin gene is performed with a positive result, prompting toxin production testing by the optimized modified Elek test.2 The latter is needed to rule out nontoxigenic tox gene-bearing strains, which are known to carry a toxin gene variant that is not fully translated, meaning there is no toxin production. While it is important to determine the toxin production status for epidemiologic purposes, in cases of suspected respiratory diphtheria, administration of diphtheria antitoxin should not be delayed until Elek test results are available, as diphtheria antitoxin treatment is time-sensitive and nontoxigenic tox gene-bearing strains are very rare.4 C. diphtheriae is a Gram-positive, non–spore-forming, nonmotile bacterium that can cause a toxin-mediated, highly contagious disease known as diphtheria, which is typically transmitted by respiratory droplets. This classically manifests as a respiratory illness with pseudomembrane formation in the nasopharyngeal region, causing severe respiratory distress together with systemic illness. Importantly, not all C. diphtheriae strains produce toxins. Toxigenic strains are particularly virulent because when the toxin enters the bloodstream, it is prone to disseminate to the heart, peripheral nerves and kidneys, and multiorgan failure can ensue. Therefore, patients with respiratory diphtheria should always receive diphtheria antitoxin in addition to antibiotic therapy. Less known is the cutaneous form of diphtheria, which is transmitted by skin-to-skin contact or contact with wound exudate. Cutaneous infections with toxigenic C. diphtheriae rarely result in severe complications because absorption of toxin into the circulation is very unlikely. Therefore, diphtheria antitoxin treatment is usually not indicated in cutaneous disease. However, antibiotic treatment should always be initiated in patients with cutaneous diphtheria to prevent the development of chronic, nonhealing wounds, bacterial spread into the patients’ circulation and bacterial shedding and transmission. Moreover, cutaneous disease can coincide with nasopharyngeal colonization, allowing respiratory transmission of the pathogen and subsequent respiratory disease in infected bystanders. Therefore, fast and stringent procedures are to be followed in suspected cases of diphtheria, including screening of close contacts, screening for nasopharyngeal colonization and, depending on the results, prophylactic antibiotic treatment (eg, azithromycin) of close contacts.5 C. diphtheriae is quite resistant to drying, and as a result, bacteria and their toxins can be isolated from the environment of infected, symptomatic patients for several weeks. This implies that healthcare professionals handling patients with suspected toxigenic diphtheria should adhere to adequate preventative measures for droplet infections. Very seldom has a laboratory-acquired diphtheria infection been reported.6 Therefore, laboratory samples and products thereof (eg, cultures) suspected of C. diphtheriae should be handled in a biologic safety cabinet by an experienced lab technician wearing appropriate personal protective equipment, including a lab coat, protective gloves and eye protection. Aerosol formation should be avoided as much as possible. Introduction of the acellular Diphtheria-Tetanus-Pertussis vaccine in the early 1990s has led to a fast decline in cases to the point it became a rare disease in regions with high vaccine coverage.7 In recent years, an increase of mostly cutaneous diphtheria cases has been reported among migrants in Europe.8 In Belgium, 22 cases of cutaneous diphtheria caused by C. diphtheriae were reported in 2022, and 11 in 2023–2024, of only 37 such cases since 2010. The majority of the 2022 cases represent refugees from countries with suboptimal immunization coverage.9 Indeed, incomplete vaccination is estimated to double the risk of diphtheria.10 Our patient was fully vaccinated according to the schedule recommended by the Belgian Superior Health Council, which includes vaccination at 8, 12 and 16 weeks of age and boosters at 15 months and 6 years of age. In Belgium, the vaccination coverage among 1-year-old children was reported to be 98%. In contrast, in Mali, the vaccination coverage was only 77%.11 Vaccination is highly protective against severe diphtheria (approximately 81%) and death (approximately 93%), but it does not prevent infection or colonization.12 Carriage rates in the vaccinated population remain unknown.13 Importantly, diphtheria toxoid vaccines do not protect against nontoxigenic strains. Nevertheless, nontoxigenic C. diphtheriae infections can also cause severe complications and are increasingly reported.14 Interestingly, cutaneous diphtheria is reported to make up a more substantial proportion of diphtheria cases in countries with high immunization coverage.15 This raises the question whether, while respiratory and systemic toxin-driven diphtheria have almost disappeared, vaccination may be less effective in preventing cutaneous disease.16 Skin problems or cutaneous manifestations of systemic infections are the third most common health issue encountered by travellers.17 The differential diagnosis for blistering lesions in a child returning from the Sahel remains very broad, with the top of the list being the usual bacterial suspects such as Staphylococci or Streptococci. However, a more rapid progression of the lesions would be expected with such causative organisms. Scabs on isolated lesions could also fit a coxsackie viral infection or Gianotti Crosti syndrome; however, involvement of multiple extremities and the face would be more common. Cutaneous nontuberculous mycobacterial infections can present with seemingly benign lesions; however, these mostly develop much more slowly. Tunga penetrans sand fly infestations can cause similar grayish lesions, often grouped together, are transmitted by walking barefoot and are endemic in the traveled region. But they mostly develop on the soles of the feet. Insect bites could show a similar clinical picture, but are generally more severe and a bite mark or history of a bite/acute pain would be expected with a less indolent course. Additionally, a rare but potentially life-threatening cause would be gangrenous lesions by soil-borne bacteria such as Clostridium perfringens, ubiquitously present in mud. Yet again, a more rapid course would be expected as well. Coming from a Central-African region, Mpox-related lesions should also be considered, as the 2024 Mpox outbreak was declared a Public Health Emergency of Continental Security by the World Health Organization.18 Nevertheless, reported cases remain limited in Mali.19 Other infectious diseases with ulcerative dermatoses often reported in African settings include cutaneous anthrax, a zoonotic infection caused by Bacillus anthracis, cutaneous leishmaniasis, a parasitic infection transmitted by sand fly bites, mycoses such as blastomycosis and finally, cutaneous diphtheria, caused by C. diphtheriae or zoonotic Corynebacterium species (eg, Corynebacterium pseudotuberculosis and Corynebacterium ulcerans), as was the case in this 10-year old boy.20 Cutaneous diphtheria is not always easy to differentiate from the usual suspects of blistering lesions, but it is highly contagious and should be included in the broad differential diagnosis of infectious skin lesions in pediatric (and adult) travelers, regardless of vaccination status. In our patient, fast multidisciplinary action and stringent isolation measures aided in quick identification of a cutaneous diphtheria case and brought the transmission chain to an end.