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Volume 29, Number 8—August 2023
CME ACTIVITY - Synopsis

Clinical Characteristics of Corynebacterium ulcerans Infection, Japan

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Discussion
CME Follow Up
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Author affiliations: National Institute of Infectious Diseases, Tokyo, Japan (A. Yamamoto, M. Ato, M. Iwaki, M. Senoh); St. Luke’s International Hospital, Tokyo (T. Hifumi, N. Otani); Ageo Central Genral Hospital, Saitama, Japan (A. Hatanaka); Oita University Faculty of Medicine, Oita, Japan (S. Nureki); International University of Health and Welfare School of Medicine, Chiba, Japan (Y. Noguchi); Japanese Red Cross Otsu Hospital, Shiga, Japan (T. Hirose); Yokohama Municipal Citizen’s Hospital, Kanagawa, Japan (Y. Yoshimura); Tsuruoka Municipal Shonai Hospital, Yamagata, Japan (T. Urakawa); Japan Community Healthcare Organization Ritsurin Hospital, Kagawa, Japan (S. Hori); Holon Toriizaka Clinic, Tokyo (H. Nakada); Tokushima Prefectural Central Hospital, Tokushima, Japan (T. Terada); Itabashi Medical System Tokyo–Katsushika General Hospital, Katsushika, Tokyo (T. Ishifuji); Kawakita General Hospital, Suginami, Tokyo (H. Matsuyama); Furano Hospital, Hokkaido, Japan (T. Kinebuchi); Dokkyo Medical University, Tochigi, Japan (A. Fukushima, K. Wake); Hospital of University of Occupational and Environmental Health, Fukuoka, Japan (K. Otsuji, T. Endo); Japanese Red Cross Ise Hospital, Mie, Japan (H. Toyoshima); Fukushima Medical University, Fukushima, Japan (I. Yasuda); Nagasaki University Hospital, Nagasaki, Japan (T. Tanaka); Kimitsu Chuo Hospital, Chiba (N. Tanaka); Tottori University Hospital, Tottori, Japan (K. Okada); Maebashi Red Cross Hospital, Gunma, Japan (T. Hayashi); Chiba Children’s Hospital, Chiba (T. Kusano); Chiba Rousai Hospital, Chiba (M. Koriyama); Kumamoto Health Science University, Kumamoto, Japan (M. Takahashi)

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Introduction

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Release date: July 21, 2023; Expiration date: July 21, 2024
Learning Objectives

Upon completion of this activity, participants will be able to:

  • Assess the demographic and clinical characteristics of patients with Corynebacterium ulcerans infection, based on a case series of 34 patients in Japan from 2001 to 2020

  • Compare clinical characteristics between patients with respiratory and nonrespiratory symptoms of Corynebacterium ulcerans ans infection and among 3 severity subgroups of patients with respiratory symptoms, based on a case series of 34 patients in Japan from 2001 to 2020

  • Determine the clinical and treatment implications of clinical characteristics, treatment-related factors, and outcomes of Corynebacterium ulcerans infection, based on a case series of 34 patients in Japan from 2001 to 2020

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Jude Rutledge, BA, Technical Writer/Editor, Emerging Infectious Diseases. Disclosure: Jude Rutledge, BA, has no relevant financial relationships.

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Laurie Barclay, MD, freelance writer and reviewer, Medscape, LLC. Disclosure: Laurie Barclay, MD, has no relevant financial relationships.

Authors

Akihiko Yamamoto, DVM, PhD; Toru Hifumi, MD, PhD; Manabu Ato, MD, PhD; Masaaki Iwaki, PhD; Mitsutoshi Senoh, PhD; Akio Hatanaka, MD, PhD; Shinichi Nureki, MD, PhD; Yoshihiro Noguchi, MD, PhD; Tomoko Hirose, MD, PhD; Yukihiro Yoshimura, MD, PhD; Takaaki Urakawa, MD, PhD; Shiro Hori, MD, PhD; Hiroto Nakada, MD, PhD; Tomomasa Terada, MD, PhD; Tomoko Ishifuji, MD, PhD; Hisayo Matsuyama, MD, PhD; Takahiro Kinebuchi, BS; Atsuhito Fukushima, MD, PhD; Koji Wake, MD, PhD; Ken Otsuji, MD, PhD; Takeru Endo, MD, PhD; Hirokazu Toyoshima, MD, PhD; Ikkoh Yasuda, MD, PhD; Takeshi Tanaka, MD, PhD; Naoki Takahashi, MD, PhD; Kensaku Okada, MD, PhD; Akihiko Yamamoto, DVM, PhD; Toru Hifumi, MD, PhD; Manabu Ato, MD, PhD; Masaaki Iwaki, PhD; Mitsutoshi Senoh, PhD; Akio Hatanaka, MD, PhD; Shinichi Nureki, MD, PhD; Yoshihiro Noguchi, MD, PhD; Tomoko Hirose, MD, PhD; Yukihiro Yoshimura, MD, PhD; Takaaki Urakawa, MD, PhD; Shiro Hori, MD, PhD; Hiroto Nakada, MD, PhD; Tomomasa Terada, MD, PhD; Tomoko Ishifuji, MD, PhD; Hisayo Matsuyama, MD, PhD; Takahiro Kinebuchi, BS; Atsuhito Fukushima, MD, PhD; Koji Wake, MD, PhD; Ken Otsuji, MD, PhD; Takeru Endo, MD, PhD; Hirokazu Toyoshima, MD, PhD; Ikkoh Yasuda, MD, PhD; Takeshi Tanaka, MD, PhD; Naoki Takahashi, MD, PhD; Kensaku Okada, MD, PhD; Toshimasa Hayashi, MD; Taizo Kusano, MD, PhD; Minami Koriyama, MD, PhD; Norio Otani, MD, PhD; and Motohide Takahashi, DVM, PhD.

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Abstract

Corynebacterium ulcerans is a closely related bacterium to the diphtheria bacterium C. diphtheriae, and some C. ulcerans strains produce toxins that are similar to diphtheria toxin. C. ulcerans is widely distributed in the environment and is considered one of the most harmful pathogens to livestock and wildlife. Infection with C. ulcerans can cause respiratory or nonrespiratory symptoms in patients. Recently, the microorganism has been increasingly recognized as an emerging zoonotic agent of diphtheria-like illness in Japan. To clarify the overall clinical characteristics, treatment-related factors, and outcomes of C. ulcerans infection, we analyzed 34 cases of C. ulcerans that occurred in Japan during 2001–2020. During 2010–2020, the incidence rate of C. ulcerans infection increased markedly, and the overall mortality rate was 5.9%. It is recommended that adults be vaccinated with diphtheria toxoid vaccine to prevent the spread of this infection.

Diphtheria is an upper respiratory tract illness caused by toxin-producing Corynebacterium diphtheriae bacteria, and it is characterized by sore throat, fever, and formation of a pseudomembrane on the tonsils, pharynx, or both, along with nasal discharge. C. diphtheriae can also infect the skin, causing open sores or ulcers. However, diphtheria skin infections rarely result in any other severe disease (1). C. ulcerans is a closely related bacterium to C. diphtheriae, and some strains produce toxins that are very similar to diphtheria toxin (2,3). C. ulcerans is widely distributed in the environment and is considered one of the most harmful pathogens to livestock and wildlife. This bacterium can cause cutaneous inflammation, including mastitis, in dairy cows (4–6). C. ulcerans has been increasingly recognized as an emerging zoonotic agent of diphtheria-like illness in the world (7–18).

Infections caused by these 2 bacteria are difficult to distinguish clinically, and the World Health Organization (WHO) treats infections caused by toxin-producing C. ulcerans as part of the diphtheria case definition (19). C. diphtheriae is thought to be transmitted only among humans, but C. ulcerans can be transmitted to humans by nonhuman mammals and thus should be treated as a zoonosis (7–18). Dogs and cats as companion animals are considered the major causes of transmission to humans. Although there have been several reports of individual cases of C. ulcerans infection (20–24), information on clinical features, treatment-related factors, and outcomes is limited. In this study we elucidate the clinical features, treatment-related factors, and outcomes of C. ulcerans infection cases in Japan during 2001–2020.

Methods

This study was a retrospective, observational, national survey of C. ulcerans infections in Japan since the first reported case of this infection (25). The data acquisition period was 20 years, from February 2001 through December 2020. The institutional review board of St. Luke’s International Hospital (Tokyo, Japan) approved this cross-sectional, survey-based study (approval no. 19-R055).

Patients and Setting

The National Institute of Infectious Disease (NIID) has comprehensively organized research and controlled clinical practice in C. ulcerans infectious diseases in Japan. However, in Japan, C. ulcerans infection is not included in the diphtheria case definition, nor is it required to be reported in all cases, so there is no obligation to report. However, because C. ulcerans produces diphtheria toxin, it has clinical manifestations similar to those caused by C. diphtheriae, for which all cases must be reported in Japan (19). Therefore, Japan’s Ministry of Health, Labour and Welfare (MHLW) urged health management departments and hospitals throughout the country to call attention to the need to identify the causative bacterium in patients showing clinical symptoms similar to diphtheria. MHLW has also published diagnostic criteria for C. ulcerans to assist clinicians in classifying C. diphtheriae and C. ulcerans (26). Under those circumstances, information from doctors who treated patients with suspected diphtheria symptoms and requests for pathogen diagnosis were sent to NIID. Therefore, the data included in this analysis came from attending physicians who, at the time of care, chose to investigate and report cases as C. ulcerans infections.

Data Collection

The following parameters were recorded: age; sex; date of infection; location of patient’s origin; whether there was a companion animal; whether there was any interaction with animals, such as breeding livestock animals, or whether the patient had lived in an environment involving contact with animals; presence or absence of bacterial isolation from patients and related animals; and clinical symptoms (throat pain, nasal discharge, pseudomembrane, fever, headache, dyspnea, hoarseness, and abscess). In addition, we collected data on vital signs (heart rate, systolic blood pressure, temperature, and respiratory rate), laboratory data (leukocyte counts, platelet counts, creatinine kinase levels, C-reactive protein [CRP] levels), types of antibiotics administered, presence or absence of administration of diphtheria antitoxin, and outcomes (days of hospitalization, days of mechanical ventilation, and survival or death).

Diagnosis of C. ulcerans Infection

The diagnostic criteria for the cases collected in this study used the C. ulcerans diagnostic criteria of MHLW (26). Accordingly, several conditions must be met: the infection manifests the same clinical symptoms as respiratory diphtheria with intractable pharyngeal pseudomembrane formation, and gram-positive rods are isolated from local areas, such as the pharynx and nasal cavity, and identified as C. ulcerans; the isolated bacterium is C. ulcerans alone, or C. ulcerans is the main component; detection of the diphtheria toxin gene and its toxin activity have been confirmed from this isolated strain by a functional test (i.e., an Elek test or equivalent test) (1,26); and cutaneous signs and symptoms are present and C. ulcerans is identified as the causative agent of local lymphadenopathy and abscesses (27,28).

Definitions of Symptoms

C. ulcerans infections are classified into respiratory and nonrespiratory manifestations. We defined respiratory symptoms as dyspnea, hoarseness, sore throat, cough, fever, and (occasionally) white pseudomembrane of the nasopharynx and laryngeal vestibule. Nonrespiratory symptoms were defined as skin infections and abscesses, or symptoms in patients who did not show respiratory symptoms. We further classified both types of symptoms as mild (resolving on outpatient visits), moderate (requiring hospitalization), or severe (requiring hospitalization and further ventilator support). The definitions of all cases included in this study were those we described previously as consistent with diagnosis of C. ulcerans infection.

Treatment of C. ulcerans Infection

For treatment of C. ulcerans infection, administration of antibiotics to which C. ulcerans is susceptible, such as macrolides and penicillins, is effective. In severe cases, symptomatic treatment for diphtheria pneumonia and administration of diphtheria antitoxin are effective for ventilated patients. The antitoxin used for C. ulcerans infection and for diseases caused by C. diphtheriae is delivered from the nearest national stockpile. However, depending on the distance, sometimes immediate delivery cannot be achieved.

Primary Data Analysis

We compared patients’ characteristics, treatment-related factors, and outcomes between the respiratory symptoms group and nonrespiratory symptoms group by using the Mann–Whitney U test or Fisher exact test, as appropriate. We used quantitative properties in the calculation basically as they are and quantified qualitative properties by scoring and then analyzed them. In the respiratory symptoms group, we compared mild, moderate, and severe cases. Regarding the collection of clinical data, we did not impute missing data. We performed statistical analysis by using JMP Pro statistical software version 14 (SAS Institute, https://www.sas.com). We considered 2-sided p values <0.05 to be statistically significant.

Results

Demographic and Clinical Characteristics of Patients

A total of 34 patients from 34 hospitals were identified during the 20-year study period (Appendix Table). The reports of C. ulcerans infections came from a wide range of areas, and there was no regional bias (Figure 1). Furthermore, when we compared the number of C. ulcerans cases every 5 years, we found the number of cases during 2001–2010 was stable (4 total cases), but the number of cases during 2011–2015 was 7 and during 2016–2020 was 19. Therefore, compared with the number of cases during 2001–2010, the number during 2011–2015 was 1.75 higher and during 2016–2020 was 4.75 times higher (Figure 2).

The symptoms of C. ulcerans infection were respiratory in 23 (67.7%) patients and nonrespiratory in 11 (32.3%) (Table 1). The median age of patients was 58 years, and 61.3% of patients were women. Almost all patients (97.1%) had contact with animals. The mortality rate was 5.9%.

Details of C. ulcerans Infection Cases

We divided the clinical characteristics of C. ulcerans patients into respiratory and nonrespiratory groups. The characteristics of respiratory symptoms include formation of pseudomembrane in addition to dyspnea, hoarseness, sore throat, and fever. In general, among the patients evaluated in our study, the pseudomembrane was often attached to the nasopharynx (Figure 3, panels A, B; Figure 4). Moreover, in severe cases, bronchoscopy showed a pseudomembranous material obstructing the bronchi (Figure 3, panel C).

Patients with pseudomembranes with bronchial obstruction were characterized by atelectasis (i.e., when part or all of the lung was devoid of air and collapses) on radiographs (Figure 4, panel A). A common cause of atelectasis was bronchial obstruction. Atelectasis spreads throughout the lungs as symptoms worsen (Figure 4, panels B, C). As lung function declines, ventilators and extracorporeal membrane oxygen therapy are required to save the patient’s life. Complications after C. ulcerans treatment have been reported (29); in that particular case, the patient reported dyspnea, and a thick pseudomembrane was found in the larynx. C. ulcerans producing diphtheria toxin was detected in the pseudomembranes. Antibiotic treatment improved airway symptoms, but sudden cardiac arrest occurred, followed by dyspnea and seizures. Afterward, the patient’s general condition stabilized, but she remained unconscious.

In contrast, nonrespiratory C. ulcerans patients evaluated in our study had local lymph node abscesses near the trauma, parotid abscesses, axillary abscesses, cervical lymph node abscesses, plantar skin ulcers, subcutaneous abscesses, and mandibular abscesses. Symptoms such as abscess, thigh abscess, and purulent lymphadenitis in the right neck were observed (Appendix). MRI images of a patient’s elbow showed abscesses in the axillary and parotid lymph nodes (Figures 4, panels E–F).

Comparing Clinical Characteristics between Respiratory and Nonrespiratory Symptoms Groups

Patients in the respiratory symptoms group were significantly older than patients in the nonrespiratory group (64 [interquartile range (IQR) 54–72] years vs. 38 [IQR 21–61] years; p = 0.03). When we compared the 3 severity classifications for respiratory and nonrespiratory symptoms, we found the group with respiratory symptoms had 6 patients with mild, 7 patients with moderate, and 10 patients with severe symptoms. In contrast, in the nonrespiratory symptom group, there were 5 mild cases, 6 moderate cases, and 0 severe cases. The differences in the number of mild, moderate, and severe cases of symptom severity in the 2 groups were significant (p<0.01) (Table 1). Leukocyte counts and CRP levels were relatively higher in the respiratory group than in the nonrespiratory group (p = 0.07 for both) (Table 1).

Comparing Clinical Characteristics among the 3 Severity Groups

Within the group showing respiratory symptoms, we compared clinical characteristics for the mild, moderate, and severe subgroups (Table 2). Among the respiratory group patients with pseudomembrane, 5 had mild cases, 6 had moderate cases, and 10 had severe cases. Among cases with respiratory symptoms, pseudomembrane-positive patients accounted for 83.3% of mild cases, 85.7% of moderate cases, and 100% of severe cases. Laboratory data showed a significant difference among the 3 subgroups in CRP levels (4.7 mg/dL [IQR 0.9–6.1 mg/dL] in mild, 7.7 mg/dL [IQR 1.8–12.6 mg/dL] in moderate, and 21 mg/dL [IQR 11.7–25.4 mg/dL] in severe cases; p = 0.02). Macrolide antibiotics, which are effective for C. ulcerans, were mainly used for mild cases. As the severity increased, many additional antibiotics, such as penicillin, cephalosporin antibiotics, and quinolone, were used. Regarding the length of hospital stay, we observed a significant difference between moderate cases (7 [IQR 7–10] days) and severe cases (29 [IQR 20–56] days; p<0.01). Diphtheria antitoxin was administered only to 4 severe case-patients (cases 5, 24, 29, and 33).

Two deaths from C. ulcerans infection occurred among the severe case-patients (20%; cases 5 and 18). Case-patient 5 was administered 5,000 IU of diphtheria antitoxin on her second day of hospitalization. C. ulcerans, which had been detected in the pseudomembrane, became negative in culture 1 week later, but the patient died on the 21st day of hospitalization without improvement in her severe pneumonia. Case-patient 18 was not administered antitoxin. She was administered antibiotics but died on the third day of her hospitalization from severe dyspnea caused by a pseudomembrane obstructing her airway (30).

Discussion

To compare our findings to those from other countries, we reviewed reports on diphtheria from the United Kingdom (31,32) and Belgium (33). Because of the history of the diphtheria pandemic in Eastern Europe in the late 1980s, surveillance of reports of C. diphtheriae infection are still underway in Europe, and cases continue to be identified. Therefore, the literature cases from this region during that period also contain reports of disease caused by the diphtheria toxin–producing C. diphtheriae and C. ulcerans (31). In Japan, the most recent case report of C. diphtheriae infection was in 2000 (34), and since then, the number of C. ulcerans infections have been increasing, as shown in our study (Figure 2). The annual trend in the number of cases of C. ulcerans infection in the United Kingdom has also increased over the past few decades (31,32). In contrast, in Belgium, the number of cases reported during 2010–2017 hardly increased (33) and has remained fairly constant.

When we compared the age of patients with C. ulcerans infection, we found that in the United Kingdom, 60% of those affected are <15 years of age, whereas in Belgium, 90% of those affected are >45 years of age. In Japan, as in Belgium, 80% of those infected are >45 years of age. The sex ratio of patients showed similar trends in all countries; women accounted for 75% of infections in the United Kingdom, 77% in Belgium, and 67% in Japan. Martini et al. (33) argued that women are more likely to be patients because they tend to have more contact with companion animals than men.

When we compared transmission routes of C. ulcerans, we found that in the past in the United Kingdom, infections were mainly caused by cattle and poorly sterilized dairy products, but in recent years, infections have been mainly caused by companion animals such as cats and dogs. The same trends occurred in Belgium and Japan. The change over time in the source of C. ulcerans infection in the United Kingdom indicates that this infection is not limited to persons involved in livestock farming and that the general public can become infected (32). We speculate that this change contributed to the recent increase in C. ulcerans infections in the United Kingdom. Because C. ulcerans infections in countries such as the United Kingdom, Belgium, and Japan are suspected to be transmitted from companion animals, not only physicians but also veterinarians who examine companion animals should be informed about C. ulcerans infection (8,11,16).

Regarding the prognosis of C. ulcerans infection, mortality rates were 6% in the United Kingdom during 1986–2017 (31,32) and 5.9% in Japan during 2001–2020. No deaths from C. ulcerans infections were reported in Belgium during 2010–2017 (33). Further details of the course of fatal cases of C. ulcerans infection in the United Kingdom show that all of the fatal cases were in women >70 years of age who had respiratory symptoms, the death of nearly one third of patients overall was possibly associated with delayed administration of antitoxin, and the death of nearly two thirds of patients overall may have been associated with delayed diagnosis of diphtheria (31,32). By comparison, 2 fatal cases in Japan occurred in women 57 and 66 years of age who had respiratory symptoms; 1 death may have been attributable to delay in administration of antitoxin, and the other death may have been because the patient was diagnosed with C. ulcerans infection too late.

When we compared cases of C. ulcerans infection in the United Kingdom and Japan in terms of deaths, we observed a similar course of death in both countries. Administration of antitoxin is the primary treatment for diphtheria, but because diphtheria antitoxin is a preparation made from horse serum immunized with diphtheria toxin, its administration may be accompanied by adverse events, such as serum sickness. The decision requires judgment in considering the risks and benefits of antitoxin administration. In the United Kingdom and Japan, 94% of patients with C. ulcerans infection survive. In both cases, administration of macrolide antibiotics is the main treatment method, whereas diphtheria antitoxin is administered to severely ill patients (31,32)

When we compared the symptoms caused by C. ulcerans infection, we found that ≈80% of patients in the United Kingdom had respiratory symptoms and ≈20% had nonrespiratory symptoms. We noted the same tendency in cases in Japan (respiratory symptoms in 66% of patients and nonrespiratory symptoms in 34%). In Belgium, on the contrary, prevalence of nonrespiratory symptoms were as high as 64%, and respiratory symptoms were observed in 36% of cases (31–33). The different proportions of respiratory and nonrespiratory symptoms of C. ulcerans infection in the 3 countries may be related to the immunologic status of patients with respect to diphtheria toxin. In our study, the patients with respiratory symptoms were mostly elderly and severely ill, whereas the patients with nonrespiratory symptoms were relatively young, and few were severely ill (Table 1). In Japan, young persons have high levels of antibody titers against diphtheria toxin, but this antibody titer declines with age (35). Patients with high antibody titers who have C. ulcerans may show nonrespiratory symptoms without exacerbation of respiratory symptoms. Different diphtheria toxoid vaccination schedules in the United Kingdom and Belgium may also influence symptoms after C. ulcerans infection (37,38).

We also considered the status of vaccination for C. ulcerans infections. The diphtheria vaccine in Japan became available in 1948, and after several changes in the inoculation content, the formulation now in use was implemented in 1995. The current vaccination schedule in Japan is to inoculate 3 times at intervals of 3–8 weeks starting at 3 months of age and to give the fourth inoculation 1 year after the third inoculation. At 11 years of age, children receive a fifth boost and are not vaccinated after that point (35). In Japan, to understand the state of immunity to diphtheria toxoid, a certain number of persons are randomly selected from prefectures nationwide and their antibody titers are measured every 4–5 years. That survey is commissioned by the government of Japan and is conducted by NIID and local health authorities. According to those survey data, the proportion of persons in their 50s who still had antibody titers at a level protective against diphtheria decreased to ≈10% (36). When we interviewed patients in our study and asked about their vaccination status, most of the patients >60 years of age, except for the 20-year-old patient in case 13 and the 6-year-old patient in case 14, so vaccination status was usually unknown. In addition, the average age of patients in our study with severe respiratory symptoms was 67 years (Table 2), and patients born before 1948 had not been vaccinated. We hypothesize that persons in the older age group are inadequately vaccinated or unvaccinated against diphtheria toxin and that the characteristics of C. ulcerans infection are related to the vaccination system in Japan.

According to reports on C. ulcerans infection in the United Kingdom and Belgium, many patients, especially those who died or were severely ill, were unvaccinated or inadequately vaccinated (31–33). The vaccination schedule in the United Kingdom is to inoculate 4 times until 5 years of age; at the age of 14, persons receive a fifth booster and are not vaccinated after that point (37). The vaccination schedule in Belgium is to inoculate 6 times until at the age of 14–16 years. Adults in Belgium are recommended to be vaccinated with a diphtheria toxoid–containing vaccine every 10 years (38). When we compared the diphtheria toxoid vaccination schedule in the United Kingdom and Belgium with Japan, we found that the United Kingdom schedule is very similar to that of Japan, but the Belgium schedule is similar to the WHO-recommended schedule and the US Advisory Committee on Immunization Practices schedule and includes vaccination for adults. This difference may explain why the number of patients with C. ulcerans infection in Belgium has remained constant over the past decade or so (38).

In light of those findings, it appears that C. ulcerans infections tend to affect generations with reduced levels of diphtheria antitoxin antibodies. Moreover, because the risk for severe disease from C. ulcerans infections increases with age, we recommend that adults be vaccinated with diphtheria toxoid vaccine to prevent the spread of this infection. In fact, the European Union (which includes Belgium), the US Centers for Disease Control and Prevention, and WHO recommend that adults be vaccinated with a diphtheria toxoid–containing vaccine every 10 years after completing the initial vaccination series in childhood (1,19,35,38).

Among the limitations of this research, we summarized clinical data on 34 cases of C. ulcerans infection reported in Japan over a 20-year period, and we reported the clinical features, treatments performed, and prognoses of these cases. However, not all cases were captured, and some data on the reported cases may have been incomplete, which may affect the reliability of our findings. Therefore, it is necessary to verify our findings with more case information in the future.

In Japan, diphtheria caused by diphtheria toxin–producing C. diphtheriae occurred in ≈100,000 patients around 1945, and ≈10% of them died. This form of diphtheria was significantly reduced by regular vaccination with the diphtheria toxoid vaccine, and the last such case was reported in 2000 (34). Meanwhile, C. ulcerans infections have been increasing over the past 20 years and have replaced disease cases caused by C. diphtheriae. Clinicians and various local hygiene agencies have been alerted to this kind of infection. However, the law does not require all cases to be reported. Given the increased number of cases revealed in our study and the WHO position of considering C. ulcerans infections to be diphtheria, we suggest that all C. ulcerans cases should be included with the infections that currently must be reported immediately.

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Acknowledgments

We thank Shouji Asakura, Tetsu Aizawa, Teruyuki Ishii, and Takehiko Morioka for their contributions to this article.

This research was conducted as one of the antitoxin research projects under Japan’s Agency for Medical Research and Development 2019–2021 Research Development of Innovative Drugs for Emerging and Reemerging Infectious Diseases Promotion research project (project no. 21fk0108101j0003).

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References

  1. Centers for Disease Control and Prevention. Diphtheria [cited 2021 Oct 20]. https://www.cdc.gov/diphtheria/index.html
  2. Wong  TP, Groman  N. Production of diphtheria toxin by selected isolates of Corynebacterium ulcerans and Corynebacterium pseudotuberculosis. Infect Immun. 1984;43:1114–6. DOIPubMedGoogle Scholar
  3. Sing  A, Bierschenk  S, Heesemann  J. Classical diphtheria caused by Corynebacterium ulcerans in Germany: amino acid sequence differences between diphtheria toxins from Corynebacterium diphtheriae and C. ulcerans. Clin Infect Dis. 2005;40:325–6. DOIPubMedGoogle Scholar
  4. Hommez  J, Devriese  LA, Vaneechoutte  M, Riegel  P, Butaye  P, Haesebrouck  F. Identification of nonlipophilic corynebacteria isolated from dairy cows with mastitis. J Clin Microbiol. 1999;37:954–7. DOIPubMedGoogle Scholar
  5. Hart  RJ. Corynebacterium ulcerans in humans and cattle in North Devon. J Hyg (Lond). 1984;92:161–4. DOIPubMedGoogle Scholar
  6. Higgs  TM, Smith  A, Cleverly  LM, Neave  FK. Corynebacterium ulcerans infections in a dairy herd. Vet Rec. 1967;81:34–5. DOIPubMedGoogle Scholar
  7. Aaron  L, Heurtebise  F, Bachelier  MN, Guimard  Y. [Pseudomembranous diphtheria caused by Corynebacterium ulcerans.] [in French]. Rev Med Interne. 2006;27:333–5. DOIPubMedGoogle Scholar
  8. Lartigue  M-F, Monnet  X, Le Flèche  A, Grimont  PAD, Benet  JJ, Durrbach  A, et al. Corynebacterium ulcerans in an immunocompromised patient with diphtheria and her dog. J Clin Microbiol. 2005;43:999–1001. DOIPubMedGoogle Scholar
  9. Morris  WE, Uzal  FA, Cipolla  AL. Pyogranulomatous meningoencephalitis in a goat due to Corynebacterium ulcerans. Vet Rec. 2005;156:317–8. DOIPubMedGoogle Scholar
  10. Foster  G, Patterson  T, Howie  F, Simpson  V, Davison  N, Efstratiou  A, et al. Corynebacterium ulcerans in free-ranging otters. Vet Rec. 2002;150:524.PubMedGoogle Scholar
  11. Taylor  DJ, Efstratiou  A, Reilly  WJ. Diphtheria toxin production by Corynebacterium ulcerans from cats. Vet Rec. 2002;150:355.PubMedGoogle Scholar
  12. Tejedor  MT, Martin  JL, Lupiola  P, Gutierrez  C. Caseous lymphadenitis caused by Corynebacterium ulcerans in the dromedary camel. Can Vet J. 2000;41:126–7.PubMedGoogle Scholar
  13. Bergin  IL, Chien  CC, Marini  RP, Fox  JG. Isolation and characterization of Corynebacterium ulcerans from cephalic implants in macaques. Comp Med. 2000;50:530–5.PubMedGoogle Scholar
  14. Olson  ME, Goemans  I, Bolingbroke  D, Lundberg  S. Gangrenous dermatitis caused by Corynebacterium ulcerans in Richardson ground squirrels. J Am Vet Med Assoc. 1988;193:367–8.PubMedGoogle Scholar
  15. Stănică  E, Maximesco  P, Stoian  C, Pop  A, Oprişan  R, Potorac  E. Level of antitoxic immunity and carriage of diphtheria bacilli in horses under present circumstances of dimunition of morbidity of diphtheria [in French]. Arch Roum Pathol Exp Microbiol. 1968;27:552–62.
  16. Panaitescu  M, Maximescu  P, Michel  J, Potorac  E. Respiratory pathogens in non-human primates with special reference to Corynebacterium ulcerans. Lab Anim. 1977;11:155–7. DOIPubMedGoogle Scholar
  17. Fox  JG, Frost  WW. Corynebacterium ulcerans mastitis in a bonnet macaque (Macaca radiata). Lab Anim Sci. 1974;24:820–2.PubMedGoogle Scholar
  18. May  BD. Corynebacterium ulcerans infections in monkeys. Lab Anim Sci. 1972;22:509–13.PubMedGoogle Scholar
  19. World Health Organization. Diphtheria: vaccine preventable diseases surveillance standards [cited 2021 Nov 17]. https://cdn.who.int/media/docs/default-source/immunization/vpd_surveillance/vpd-surveillance-standards-publication/who-surveillancevaccinepreventable-04-diphtheria-r2.pdf
  20. Lartigue  MF, Monnet  X, Le Flèche  A, Grimont  PA, Benet  JJ, Durrbach  A, et al. Corynebacterium ulcerans in an immunocompromised patient with diphtheria and her dog. J Clin Microbiol. 2005;43:999–1001. DOIPubMedGoogle Scholar
  21. Vandentorren  S, Guiso  N, Badell  E, Boisrenoult  P, Micaelo  M, Troché  G, et al. Toxigenic Corynebacterium ulcerans in a fatal human case and her feline contacts, France, March 2014. Euro Surveill. 2014;19:1–3. DOIPubMedGoogle Scholar
  22. Mattos-Guaraldi  AL, Sampaio  JL, Santos  CS, Pimenta  FP, Pereira  GA, Pacheco  LG, et al. First detection of Corynebacterium ulcerans producing a diphtheria-like toxin in a case of human with pulmonary infection in the Rio de Janeiro metropolitan area, Brazil. Mem Inst Oswaldo Cruz. 2008;103:396–400. DOIPubMedGoogle Scholar
  23. Patil  SM, Beck  PP, Nelson  TB, Acevedo  AB, Roland  W. Prepatellar bursitis with abscess due to Corynebacterium ulcerans. Case Rep Orthop. 2021;2021:3507672. DOIPubMedGoogle Scholar
  24. Meinel  DM, Konrad  R, Berger  A, König  C, Schmidt-Wieland  T, Hogardt  M, et al. Zoonotic transmission of toxigenic Corynebacterium ulcerans strain, Germany, 2012. Emerg Infect Dis. 2015;21:356–8. DOIPubMedGoogle Scholar
  25. Hatanaka  A, Tsunoda  A, Okamoto  M, Ooe  K, Nakamura  A, Miyakoshi  M, et al. Corynebacterium ulcerans Diphtheria in Japan. Emerg Infect Dis. 2003;9:752–3. DOIPubMedGoogle Scholar
  26. Ministry of Health. Labour and Welfare of Japan. Q&A about Corynebacterium ulcerans [cited 2021 Dec 15]. https://www.mhlw.go.jp/bunya/kenkou/kekkaku-kansenshou18/corynebacterium_02.html
  27. Moore  LSP, Leslie  A, Meltzer  M, Sandison  A, Efstratiou  A, Sriskandan  S. Corynebacterium ulcerans cutaneous diphtheria. Lancet Infect Dis. 2015;15:1100–7. DOIPubMedGoogle Scholar
  28. Wagner  J, Ignatius  R, Voss  S, Höpfner  V, Ehlers  S, Funke  G, et al. Infection of the skin caused by Corynebacterium ulcerans and mimicking classical cutaneous diphtheria. Clin Infect Dis. 2001;33:1598–600. DOIPubMedGoogle Scholar
  29. Ohno  T, Sakamoto  M, Koyama  Y, Hatanaka  A. A case of pseudomembranous laryngitis caused by Corynebacterium ulcerans with severe systemic complications. Nippon Jibiinkoka Tokeibugeka Gakkai Kaiho. 2021;124:1413–8. DOIGoogle Scholar
  30. Yasuda  I, Matsuyama  H, Ishifuji  T, Yamashita  Y, Takaki  M, Morimoto  K, et al. Severe pneumonia caused by toxigenic Corynebacterium ulcerans infection, Japan. Emerg Infect Dis. 2018;24:588–91. DOIPubMedGoogle Scholar
  31. Wagner  KS, White  JM, Crowcroft  NS, De Martin  S, Mann  G, Efstratiou  A. Diphtheria in the United Kingdom, 1986-2008: the increasing role of Corynebacterium ulcerans. Epidemiol Infect. 2010;138:1519–30. DOIPubMedGoogle Scholar
  32. Gower  CM, Scobie  A, Fry  NK, Litt  DJ, Cameron  JC, Chand  MA, et al. The changing epidemiology of diphtheria in the United Kingdom, 2009 to 2017. Euro Surveill. 2020;25:1900462. DOIPubMedGoogle Scholar
  33. Martini  H, Soetens  O, Litt  D, Fry  NK, Detemmerman  L, Wybo  I, et al. Diphtheria in Belgium: 2010-2017. J Med Microbiol. 2019;68:1517–25. DOIPubMedGoogle Scholar
  34. National Institute of Infectious Diseases (Japan). Diphtheriae [in Japanese] [cited 2022 Nov 17]. http://idsc.nih.go.jp/iasr/19/224/tpc224-j.html
  35. National Institute of Infectious Diseases (Japan). Vaccination schedule for children in Japan [in Japanese] [cited 2022 Nov 17]. http://idsc.nih.go.jp/vaccine/dschedule.html
  36. National Institute of Infectious Diseases (Japan). Infectious disease epidemic prediction survey report [in Japanese] [cited 2022 Nov 17]. https://www.niid.go.jp/niid/ja/y-reports/669-yosoku-report.html
  37. Public Health England. The complete routine immunisation schedule 2013 to 2014 [cited 2022 Nov 17]. https://www.gov.uk/government/publications/the-complete-routine-immunisation-schedule-201314
  38. European Centre for Disease Prevention and Control. Vaccine scheduler [cited 2022 Nov 17]. https://vaccine-schedule.ecdc.europa.eu

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Article Title: 
Clinical Characteristics of Corynebacterium ulcerans Infection, Japan
CME Questions

  • Your patient is a 64-year-old man with clinical symptoms of diphtheria. On the basis of the case series of 34 patients in Japan from 2001 to 2020 by Yamamoto and colleagues, which one of the following statements about the demographic and clinical characteristics of patients with Corynebacterium ulcerans infection is correct?

    • Incidence rate remained stable during the study period

    • Mortality rate was 2%

    • About two-thirds of C. ulcerans disease was respiratory and one-third nonrespiratory

    • Nonrespiratory cases were primarily bloodstream infections

  • On the basis of the case series of 34 patients in Japan from 2001 to 2020 by Yamamoto and colleagues, which one of the following statements about clinical characteristics compared between patients with respiratory vs nonrespiratory symptoms of C. ulcerans infection, and among the 3 severity subgroups of patients with respiratory symptoms, is correct?

    • Patients in the respiratory symptom group were significantly younger than those in the nonrespiratory group

    • Cases in the respiratory symptom group were less severe than those in the nonrespiratory group

    • The 3 respiratory subgroups did not differ significantly in C-reactive protein (CRP) levels

    • 4 of 10 severe cases, but no mild (n=5) or moderate (n=6) respiratory cases, received diphtheria antitoxin

  • According to the case series of 34 patients in Japan from 2001 to 2020 by Yamamoto and colleagues, which one of the following statements about clinical and treatment implications of clinical characteristics, treatment-related factors, and outcomes of C. ulcerans infection is correct?

    • To prevent spread of C. ulcerans and Corynebacterium diphtheriae, adults should be vaccinated with diphtheria toxoid vaccine

    • All patients with moderate or severe C. ulcerans infection should receive diphtheria antitoxin

    • C. ulcerans infection in the UK, Belgium, and Japan is primarily transmitted via livestock farming

    • C. ulcerans infections do not need to be reported to public health agencies

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Cite This Article

DOI: 10.3201/eid2908.220058

Original Publication Date: July 20, 2023

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Akihiko Yamamoto, Management Department of Biosafety and Laboratory Animal, National Institute of Infectious Diseases, Tokyo, 2080011, Japan

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Page created: May 31, 2023
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