Cutaneous diphtheria from 2018 to 2022: an observational, retrospective study of epidemiological, microbiological, clinical, and therapeutic characteristics in metropolitan France.

The incidence of diphtheria has been rising over the past decade, particularly in its cutaneous form. A clinical review of the case series was therefore required. We reviewed the epidemiological, clinical, microbiological and therapeutic data of cutaneous diphtheria cases, in adult patients living in metropolitan France with a skin sample positive for corynebacteria of the diphtheriae complex between 2018 and 2022. Of the 132 cases identified, 63 met the inclusion criteria. The mean age was 53.8 years, 68.3% were men and 56.7% had travelled outside mainland France. Immunization rate was 44%. Lesions involved the lower limbs (86.9%), corresponded to ulcerations in 82% of cases. Two species were identified in the study: C. diphtheriae (77%) and C. ulcerans (23%). 39% were toxigenic. Other bacteria were present in 88.9% of cases: Staphylococcus aureus (54.7%) and Streptococcus pyogenes (49.1%). 17.5% of clinicians ignored the presence of Corynebacteria of the diphtheriae species complex. Clinicians seem to be unfamiliar with this disease due to under-reporting and a lack of knowledge and awareness among clinicians, and rarely mention it, which explains the frequent failure to comply with French recommendations. Clinical data are consistent with the literature. Continued epidemiological surveillance, increased vaccination coverage in high-risk populations and better information of clinicians are essential to prevent and control this preventable disease.

Reidentification and determination of drug susceptibility of Corynebacterium diphtheriae and Corynebacterium ulcerans strains isolated from clinical samples in 2023 in Poland. / Reidentyfikacja oraz okreslenie lekowrazliwosci szczepów Corynebacterium diphtheriae i Corynebacterium ulcerans wyizolowanych z próbek materialu klinicznego w 2023 roku w Polsce.

BACKGROUND: Despite the fact that the last cases of fully-symptomatic diphtheria were recorded in Poland in 1996 and 2000, infections caused by non-toxin-producing strains of Corynebacterium still occur. According to the epidemiological reports from ECDC in the second half of 2022, there was an increase in the number of diphtheria cases in European Union countries. As a result, the current issue becomes the appropriate preparation of microbiological laboratories for the diagnosis of Corynebacterium microorganisms. OBJECTIVE: Reidentification of diphtheria bacilli isolated from clinical samples and to assess the drug susceptibility of C. diphtheriae strains isolated in Poland. MATERIAL AND METHODS: The subject of the research were 18 strains isolated from clinical samples in Poland in 2023. Microbiological and genetic methods were used for the reidentification of the strains. Drug susceptibility was assessed using the disk diffusion method, following the new EUCAST recommendations effective from 2023. RESULTS: It was confirmed that all examined strains belonged to the genus Corynebacterium. It was de-monstrated that C. diphtheriae strains proved to be susceptible to increased exposure to benzylpenicillin and cefotaxime. Results obtained using ciprofloxacin allowed categorizing the strains into the intermediate susceptibility category WZE, except for one strain which was resistant to this antibiotic. All tested bacterial strains were susceptible to erythromycin. The C. ulcerans strain exhibited a similar antibiotic resistance profile to penicillin, cefotaxime, and ciprofloxa-cin, with additional detection of resistance to clindamycin. The toxigenicity of the tested strains was excluded. CONCLUSIONS: Based on epidemiological data regarding the emergence of new cases of infections caused by Corynebacterium strains, it is advisable to prepare theoretically and practically laboratories for diagnostics to detect potentially toxigenic diphtheria bacilli. Effective methods for the microbiological diagnosis of diphtheria bacilli are available. It is recommended to monitor the susceptibility to antimicrobial agents in all C. diphtheriae isolates.

Risk factors of diphtheria outbreak in damt district of Al Dhalea Governorate, 2023 -Yemen: a case-control study.

BACKGROUND: In Yemen, diphtheria has become an important health problem since 2017 when diphtheria re-emergence as a consequence of war and the collapse of the health system. In 2023, there has been a 57% increase in diphtheria cases compared to 2021 and 2022. Damt district of Al Dhalea Governorate had the highest reported cases for year 2023. The study aims to determine the risk factors associated with diphtheria outbreak in Damt District. METHODS: A retrospective matched case-control (1:2) was used. All confirmed cases based on the WHO case definition reported from Damt district during 2023 were considered cases. Two age-matched (± 5years) neighborhood controls were recruited per case. A pretested questionnaire was used for collecting data during household interviews including demographic and household characteristics, knowledge of diphtheria, vaccination status, contact with a case of diphtheria, and travel history. Frequency and proportion for quantitative and median with interquartile range (IQR) for quantitative variables. Chi-square and Mann-Whitney tests to compare the distribution of categorical and numerical variables between cases and controls. Univariate and multivariate conditional binary logistic regression, and Adjusted Odds ratio (AOR) with a 95% confidence interval at P < 0.05 were used to identify risk factors. RESULTS: A total of 118 cases and 236 controls were enrolled, 56% were females (63% of cases vs. 53% of controls). The median (IQR) age was 14 (9,22) years for cases vs 12(7,23) of control, it was significantly higher for females than males in the case group: (16(10,29) Vs 10(6,18), P < 0.001) and control group: (15(8,25) vs 12(7,18), p-value = 0.022). Partial vaccination status AOR = 13.7(6.1-31.1), P-value < 0.001), contacts with a case of diphtheria AOR = 8.5(2.3-31.0), P value < 0.001) and Female gender, AOR = 3.3(CI; 1.1-9.5, P value = 0.029), were the main risk factors. CONCLUSIONS: Poor vaccination and contact with a case of diphtheria were the main contributors to diphtheria in the Damt district particularly among adult females. Increasing the vaccination coverage with a diphtheria-containing vaccine through routine immunization as well as tetanus-diphtheria vaccine for childbearing age females along with community awareness regarding protection measures during home care of diphtheria cases. Vaccination services as well as gender barriers related to Td vaccination should be investigated.

Rare manifestations of cutaneous diphtheria: a case report.

BACKGROUND: This case report presents an exceptionally rare and atypical presentation of diphtheria in a 17-year-old female of Hausa ethnicity residing in an area with an elevated incidence within Kano State, Nigeria. By the end of 39th epidemiological week of 2023, only two cases of cutaneous diphtheria have been reported among 5,811 cases managed at MMSH diphtheria treatment center (DTC), representing approximately 0.035% of all diphtheria cases during that time period. CASE PRESENTATION: A 17-year-old Hausa female presented with a 3-day history of throat discomfort, malaise, and muffled speech. Physical examination revealed a pseudomembrane covering the tonsillar pillars, grade 3 tonsillar enlargement, and an unusual genital manifestation characterized by extensive vulval edema, severe pain, and a large, greyish patch extending into the vaginal introitus. Her medical history was significant for recent exposure to diphtheria and the emotional impact of her sibling's death from the same disease. Diagnostic tests, including throat swab culture and histocytology, confirmed diphtheria in the throat and vulvovaginal regions. The patient was promptly initiated on diphtheria antitoxin, Azithromycin, and innovative sitz baths with hydrogen peroxide. After 4 days of Sitz bath therapy, complete pseudomembrane clearance was observed, and the patient's symptoms resolved. CONCLUSION: This case underscores the complexity of diphtheria presentations, particularly with rare pseudomembranes in both throat and vaginal regions. The successful management, combining traditional and innovative therapies, highlights the importance of recognizing and addressing unusual manifestations promptly. The potential role of auto-inoculation and the efficacy of interventions like hydrogen peroxide sitz baths warrant further investigation. Overall, this case contributes to the understanding of diverse diphtheria presentations, guiding future clinical strategies for management of diphtheria cases and emphasizing the imperative of comprehensive vaccination efforts.

Factors Associated with the Outcome of 2023 Diphtheria Outbreak in Jigawa State, Nigeria: A Retrospective Review of the Surveillance Data.

OBJECTIVE: The objective of this study was to identify the factors associated with the outcome of the 2023 diphtheria outbreak in Jigawa State, Nigeria. METHODS: A descriptive cross-sectional study was conducted amongst all line-listed diphtheria cases reported from Jigawa State, Nigeria, using the 2023 Integrated Disease and Surveillance Response line list of cases that met the World Health Organization case definition of diphtheria. A total of 245 line-listed cases from January 2023 to December 2023 met the criteria for inclusion in the study. Data were analysed using IBM SPSS version 22.0 with a P value set at ≤5%. Binary logistic regression was used to identify the independent predictors of the outcome of the 2023 outbreak. RESULTS: The maximum age of the line-listed cases was 39 years, and the minimum was 1 year with a median of 8 (interquartile range = 5-8) years. More than two-thirds (68.2%) of the cases were ≥5 years of age. More than one-third of the cases (39.6%) were from the northeast senatorial zone of the state. Out of the total 245 cases, 14 died of the disease representing a case fatality rate of 6%, and an attack rate of 3.4 per 100,000 populations. The majority of the cases (95.5%) had fever, cough (81.2%), pharyngitis (86.9%), tonsillitis (96.7%) and laryngitis (82.0%). More diphtheria-related mortalities were recorded amongst cases <5 years of age (7.7%), female cases (5.9%), rural residence (7.7%) and cases from the northeast senatorial zone (8.2%) of the state. Significantly higher mortalities (8.8%, P = 0.003) were recorded amongst cases with nasopharyngitis. The odds of diphtheria-related mortality were higher amongst cases who presented clinically with nasopharyngitis and were 4 times more likely to die (adjusted odds ratio = 3.9; 95% confidence interval = 1.1-14.3) compared with those with no nasopharyngitis. CONCLUSIONS: Significantly higher mortalities were recorded amongst diphtheria cases whose samples were not taken, and those with nasopharyngitis. These findings underscored the importance of improved immunisation uptake, early and prompt case detection, investigation and proper management.

Determinants of mortality in relationship between clinical and laboratory characteristics with the outcomes of children with diphtheria: A cross-sectional study at a national hospital of Sumatra region in 2020- 2023.

In 2017, diphtheria outbreaks occurred in several provinces in Indonesia; however, the epidemiological data in the country is limited. The aim of this study was to determine the association between clinical findings and laboratory parameters associated with mortality of children with diphtheria. A retrospective cohort study was conducted at Haji Adam Malik General Hospital, Medan, Indonesia, covering diphtheria patients from January 2020 to December 2023. All patients aged 1-18 years clinically diagnosed with diphtheria were considered eligible. The associations between demographic characteristics, clinical features, immunization status, complications, and laboratory profiles with mortality were determined using Fisher's exact test, and the odds ratio (OR) with a 95% confidence interval (95%CI) was calculated. Our data indicated that the clinical characteristics of myocarditis (p=0.005) and airway obstruction (p=0.003) were associated with mortality. There was also a significant association between thrombocytopenia (p=0.020) and mortality in diphtheria patients. Patients with airway obstruction were 13 times more likely to have an increase in mortality compared to patients without airway obstruction. This study highlights that clinical and laboratory characteristics could be associated with in-hospital mortality of diphtheria cases, and therefore, pediatricians should be aware of the presence of those characteristics to prevent the mortality of the patients.

Seroprevalence of anti-diphtheria toxoid antibody and implications for vaccination policy in Vietnam's South-central coast: a cross-sectional study.

BACKGROUND: Diphtheria is a re-emerging infectious disease and public health concern worldwide and in Vietnam with increasing cases in recent years. This study aimed to assess the anti-diphtheria toxoid antibodies status in Khanh Hoa Province and identify factors contributing to the vaccination policy in the south-central coast of Vietnam. METHODS: This was a cross-sectional study to evaluate the seroprevalence of anti-diphtheria toxoid antibodies among 1,195 participants, aged 5 - 40 years in Khanh Hoa Province, Vietnam. Immunoglobulin G antibody levels against diphtheria were detected using a commercial anti-diphtheria toxoid enzyme-linked immunosorbent assay (SERION ELISA classic Diphtheria Immunoglobulin G) and were categorized following the World Health Organization guidelines. RESULTS: The mean anti-diphtheria toxoid antibody levels were 0.07 IU/ml (95% Confidence Interval: 0.07-0.08). Anti-diphtheria toxoid antibody levels were found to be associated with age and history of diphtheria vaccination. The 5-15 years age group had the highest levels (0.09 IU/ml), while the older age group had the lowest antibody level (p < 0.001). Individuals who received three doses (adjusted Odds ratio: 2.34, 95%CI: 1.35 - 4.07) or 4+ doses (adjusted Odds ratio: 2.45, 95%CI: 1.29 - 4.64) had a higher antibody level compared to those who received only one dose regardless of age. CONCLUSION: It is crucial to promote routine vaccination coverage to over 95% for children under one year of age with three primary doses of the diphtheria-containing vaccine, including additional doses at 18 months and 7 years of age. Booster doses should be promoted and administered to adolescents and adults every 10 years.

The Burden and Risk Factors Associated with Infectious Diseases among Refugees in a Camp for Migrants in Porto Alegre: A Cross-Sectional Survey.

Refugees usually face a disproportionate burden of infectious diseases. Recently, Brazil has experienced an influx of refugees which demands the need for scaling up public health efforts to address the challenges. The research sought to study the burden and risk factors associated with infectious diseases among refugees received in the city of Porto Alegre. This was a cross-sectional study of 261 newly arrived refugees. The study sample was predominantly composed of Venezuelans (50.6%) and Haitians (44%), male (146: 56.7%), single (30.7%), with an average age of 33.38 (± 7.30) years. The average schooling was 10.42 (± 2.09) years. Diseases with the highest prevalence were influenza, whooping cough, diphtheria, and tuberculosis. There was significant association between the country of origin and presence of symptoms for infectious and contagious diseases, which warrants targeted interventions for reducing the incidence of these diseases among refugees in Brazil.

Infection by a multidrug-resistant Corynebacterium diphtheriae strain: prediction of virulence factors, CRISPR-Cas system analysis, and structural implications of mutations conferring rifampin resistance.

Cases of diphtheria, even in immunized individuals, are still reported in several parts of the world, including in Brazil. New outbreaks occur in Europe and other continents. In this context, studies on Corynebacterium diphtheriae infections are highly relevant, both for a better understanding of the pathogenesis of the disease and for controlling the circulation of clones and antimicrobial resistance genes. Here we present a case of cutaneous infection by multidrug-resistant Corynebacterium diphtheriae and provide its whole-genome sequencing. Genomic analysis revealed resistance genes, including tet(W), sul1, cmx, rpoB2, rbpA and mutation in rpoB. We performed phylogenetic analyzes and used the BRIG to compare the predicted resistance genes with those found in genomes from other significant isolates, including those associated with some outbreaks. Virulence factors such as spaD, srtBC, spaH, srtDE, surface-anchored pilus proteins (sapD), nonfimbrial adhesins (DIP0733, DIP1281, and DIP1621), embC and mptC (putatively involved in CdiLAM), sigA, dtxR and MdbA (putatively involved) in post-translational modification, were detected. We identified the CRISPR-Cas system in our isolate, which was classified as Type II-U based on the database and contains 15 spacers. This system functions as an adaptive immune mechanism. The strain was attributed to a new sequence type ST-928, and phylogenetic analysis confirmed that it was related to ST-634 of C. diphtheriae strains isolated in French Guiana and Brazil. In addition, since infections are not always reported, studies with the sequence data might be a way to complement and inform C. diphtheriae surveillance.

Respiratory diphtheria in the time of Omicron.

Abstract: Diphtheria is a potentially fatal bacterial infection caused by toxin-producing strains of corynebacteria, most often Corynebacterium diphtheriae and less commonly Corynebacterium ulcerans. Incidence of the disease has fallen significantly since the introduction of vaccination programs; it is now rare in countries with high vaccination coverage such as Australia. This article presents the most recent respiratory cases of diphtheria in two children in New South Wales-the first locally acquired childhood cases in Australia in 30 years-and discusses potential contributing factors. These encompass the lack of clinical awareness and the delays in laboratory diagnosis in regional laboratories. The cases also highlight the problem of vaccine hesitancy and the role that primary carers play in addressing these anxieties. While clinical management of the cases progressed well, factors in the public health responses were complicated by access to appropriate care and by delays in antibiotic sensitivity profiles. The public health response to these cases raises important considerations for clinicians and public health practitioners, including preparedness for rare and re-emerging diseases, the need for culturally safe environments and the importance of addressing vaccine hesitancy. Preparedness requires consideration of the capacity of regional health systems with fewer resources and of how public health departments can support response to multiple crises. Preparedness also relies on access to necessary diagnostic laboratory resources, on up-to-date guidelines, and on maintaining awareness among clinicians for these rare infections.

Retrospective Study of Infections with Corynebacterium diphtheriae Species Complex, French Guiana, 2016-2021.

Human infections with Corynebacterium diphtheriae species complex (CdSC) bacteria were rare in French Guiana until 2016, when the number of cases diagnosed increased. We conducted an epidemiologic, multicenter, retrospective study of all human CdSC infections diagnosed in French Guiana during January 1, 2016-December 31, 2021. A total of 64 infectious episodes were observed in 60 patients; 61 infections were caused by C. diphtheriae and 3 by C. ulcerans. Estimated incidence increased from 0.7 cases/100,000 population in 2016 to 7.7 cases/100,000 population in 2021. The mean patient age was 30.4 (+23.7) years, and male-to-female ratio was 1.7:1 (38/22). Of the 61 C. diphtheriae isolates, 5 tested positive for the diphtheria toxin gene, and all results were negative by Elek test; 95% (61/64) of cases were cutaneous, including the C. ulcerans cases. The increase in reported human infections underscores the need to raise awareness among frontline healthcare practitioners to improve prevention.

Challenges of Diphtheria Toxin Detection.

Diphtheria toxin (DT) is the main virulence factor of Corynebacterium diphtheriae, C. ulcerans and C. pseudotuberculosis. Moreover, new Corynebacterium species with the potential to produce diphtheria toxin have also been described. Therefore, the detection of the toxin is the most important test in the microbiological diagnosis of diphtheria and other corynebacteria infections. Since the first demonstration in 1888 that DT is a major virulence factor of C. diphtheriae, responsible for the systemic manifestation of the disease, various methods for DT detection have been developed, but the diagnostic usefulness of most of them has not been confirmed on a sufficiently large group of samples. Despite substantial progress in the science and diagnostics of infectious diseases, the Elek test is still the basic recommended diagnostic test for DT detection. The challenge here is the poor availability of an antitoxin and declining experience even in reference laboratories due to the low prevalence of diphtheria in developed countries. However, recent and very promising assays have been developed with the potential for use as rapid point-of-care testing (POCT), such as ICS and LFIA for toxin detection, LAMP for tox gene detection, and biosensors for both.

Balto and Togo during the cold winter of Alaska (1925): the two canine heroes in the fight against diphtheria.

In recent years, diphtheria has re-emerged in areas with inadequate vaccination coverage, and Europe has not been spared with several cases among migrants. Diphtheria is a potentially fatal infection caused mainly by toxigenic strains of Corynebacterium diphtheriae. Due to the high mortality rate, especially among young children, the fight against diphtheria is considered one of the first conquests of immunization. In the history of medicine, there is a unique case of an unconventional response to a diphtheria outbreak in which sled dogs were used to overcome the supply difficulties of diphtheria antitoxin. The mass media followed the medical response to the outbreak and raised audience awareness of public health issues. The facts of Nome, Alaska, in 1925 can serve as a catalyst to rethink conventional responses to diphtheria outbreaks in low-income countries today and promote mass media awareness of public health importance.

Diphtheria in a Swiss Asylum Seeker Reception Centre: Outbreak Investigation and Evaluation of Testing and Vaccination Strategies.

Objectives: To describe a suspected diphtheria outbreak in a Swiss asylum seeker reception centre, and to analyse its management response regarding testing and vaccination. Methods: We retrospectively analysed clinical, microbiology, and case management data of all asylum seekers tested for C. diphtheriae between 28th August and 31st December 2022 while residing at the centre. Results are reported descriptively. Results: Among 265 individuals tested, ten cases of cutaneous diphtheria, one simultaneous respiratory and cutaneous case, and nine respiratory carriers were identified. Mass throat screening, targeted throat testing and targeted wound testing yielded 4.8%, 4.3%, and 17.4% positive results, respectively. No respiratory carrier was identified among cutaneous cases undergoing a throat swab, and no symptomatic case was identified among individuals with unspecific throat symptoms. Rates of vaccination implementation of newly arriving asylum seekers before and after the outbreak were low (17.5% and 15.5%, respectively), as were rates of targeted vaccination among cases and close contacts. Conclusion: We provide evidence for transmission both prior to arrival and within the setting, suboptimal practices and timeliness of testing, and implementation gaps in vaccination.

Antibody persistence to diphtheria toxoid, tetanus toxoid, Bordetella pertussis antigens, and Haemophilus influenzae type b following primary and first booster with pentavalent versus hexavalent vaccines.

Thailand has incorporated the whole-cell (wP) pertussis vaccine into the expanded program on immunization since 1977 and has offered the acellular pertussis (aP) vaccine as an optional vaccine for infants since 2001. We followed healthy children from a clinical trial (ClinicalTrials.gov NCT02408926) in which children were randomly assigned to receive either pentavalent (DTwP-HB-Hib) or hexavalent (DTaP-IPV-HB-Hib) vaccines for their primary series (administered at 2, 4, and 6 months) and first booster vaccination (18 months). Both groups received Tdap-IPV as a second booster at the age of 4 y. Blood samples were collected for evaluation of antibody persistence to diphtheria toxoid (DT), tetanus toxoid (TT), and Bordetella pertussis (B. pertussis) between 2 and 6 y of age annually, and for the immunogenicity study of Tdap-IPV at 1 month after the second booster. Antibody persistence to Haemophilus influenzae type b (Hib) was followed until 3 y of age. A total of 105 hexavalent-vaccinated children and 91 pentavalent-vaccinated children completed this study. Both pentavalent and hexavalent groups demonstrated increased antibody levels against DT, TT, and B. pertussis antigens following the second booster with Tdap-IPV. All children achieved a seroprotective concentration for anti-DT and anti-TT IgG at 1 month post booster. The hexavalent group possessed significantly higher anti-pertactin IgG (adjusted p = .023), whereas the pentavalent group possessed significantly higher anti-pertussis toxin IgG (adjusted p < .001) after the second booster. Despite declining levels post-second booster, a greater number of children sustained protective levels of anti-DT and anti-TT IgG compared to those after the first booster.