Seroprevalence of IgG antibodies against diphtheria antitoxin among migrant workers in Singapore, 2016–2019

Background Since the last local case of diphtheria in 1992, there had not been any case in Singapore until an autochthonous case was reported in 2017. This fatal diphtheria case of a migrant worker raised concerns about the potential re-emergence of locally transmitted toxigenic diphtheria in Singapore. We conducted a seroprevalence study to assess the immunity levels to diphtheria among migrant workers in Singapore. Methods Residual sera from migrant workers who hailed from Bangladesh, China, India, Indonesia, Malaysia, Myanmar and the Philippines were tested for anti-diphtheria toxoid immunoglobulin G (IgG) antibodies. These migrant workers previously participated in a survey between 2016 and 2019 and had provided blood samples as part of the survey procedure. Results A total of 2176 migrant workers were included in the study. Their overall mean age was 27.1 years (standard deviation 5.0), range was 20–43 years. The proportion having at least basic protection against diphtheria (antitoxin titres ≥ 0.01 IU/ml) ranged from 77.9% (95% confidence interval [CI] 72.8 – 82.3%) among migrant workers from Bangladesh to 96.7% (95% CI 92.5 – 98.6%) in those hailing from Malaysia. The proportion showing full protection (antitoxin titres ≥ 0.10 IU/ml) ranged from 10.1% (95% CI 6.5 – 15.4%) in Chinese workers to 23.0% (95% CI 17.1 – 30.3%) in Malaysian workers. There were no significant differences in the proportion with at least basic protection across birth cohorts, except for those from Bangladesh where the seroprevalence was significantly lower in younger migrant workers born after 1989. Conclusions The proportions having at least basic protection against diphtheria in migrant workers from five out of seven Asian countries (India, Indonesia, Malaysia, Myanmar and the Philippines) were higher than 85%, the threshold for diphtheria herd immunity. Seroprevalence surveys should be conducted periodically to assess the level of immunity against diphtheria and other vaccine preventable diseases in migrant worker population, so that appropriate interventions such as booster vaccination can be implemented proactively to prevent sporadic outbreaks.

Investigating Alternative Container Formats for Lyophilization of Biological Materials Using Diphtheria Antitoxin Monoclonal Antibody as a Model Molecule

When preparing biological reference materials, the stability of the lyophilized product is critical for long-term storage, particularly in order to meet WHO International Standards, which are not assigned expiry dates but are expected to be in use for several decades. Glass ampoules are typically used by the National Institute for Biological Standards and Control (NIBSC) [PM1] for the lyophilization of biological materials. More recently, a clear need has arisen for the filling of smaller volumes, for which ampoules may not be optimal. We investigated the use of plastic microtubes as an alternative container for small volume fills. In this study, a recombinant diphtheria antitoxin monoclonal antibody (DATMAB) was used as a model molecule to investigate the suitability of plastic microtubes for filling small volumes. The stability and quality of the dried material was assessed after an accelerated degradation study using a toxin neutralization test and size exclusion HPLC. While microtubes have shown some promise in the past for use in the lyophilization of some biological materials, issues with stability may arise when more labile materials are freeze-dried. We demonstrate here that the microtube format is unsuitable for ensuring the stability of this monoclonal antibody.

Diphtheria

Diphtheria is caused by toxin-producing bacteria, Corynebacterium diphtheriae, and less frequently by one of two other, zoonotic, Corynebacteria. Diphtheria toxin destroys tissue, which builds up in the throat and tonsils, making breathing and swallowing almost impossible. The bacteria are transmitted by respiratory droplets, by direct physical contact with skin lesions, via secretions from infected patients, or contaminated materials. Clinically, tonsillitis, pharyngitis, laryngitis, and skin infections (wound infection; ulcers) appear; diphtheria once was a terrible killer of young children. Antibiotics (penicillin, erythromycin, others) are used to eradicate the bacteria; for respiratory infections, diphtheria antitoxin is used to neutralize circulating toxins and reduce/prevent complications like myocarditis, neuritis (nerve palsies). Case fatality rates of up to 10% have been reported during diphtheria outbreaks, and are even higher in settings where diphtheria antitoxin is unavailable. Diphtheria vaccines consist of inactivated toxins, called toxoids, and are available in combinations with other antigens such as tetanus, pertussis, and others. These combinations are usually well-tolerated, local reactions are the most frequently observed side effects. Efficacy studies are not available but various observational studies consistently indicate high vaccine effectiveness between 87% and 96%.

Microbiological and Clinical Aspects of Diphtheria-Confirmed Cases from Capital City of Indonesia, Jakarta, and Surrounding Areas in 2017

Background: The World Health Organization reported Indonesia as one of the countries with the most prevalent cases of diphtheria worldwide. The microbiological aspects of diphtheria-inducing bacteria are of great significance in tracing disease transmission and case management. However, clinical aspects are critical for updating clinical features and case management in the field, which may sometimes differ from theoretical foundations. Objectives: This study aimed to identify the microbiological and clinical aspects, including molecular typing and case fatality rates, in diphtheria-confirmed cases from the capital city of Indonesia, Jakarta, and surrounding areas in 2017. Methods: The microbiological aspect of 40 diphtheria-confirmed cases were obtained by re-identify diphtheria-inducing bacteria isolated from the samples, while the clinical aspects of the cases were obtained from the medical records and epidemiological data. The chi-square test was used to examine the correlation between fatal cases and myocarditis and diphtheria antitoxin administration delay. In this study, P ≤ 0.05 was set as the significance level. Results: All 40 diphtheria confirmed cases were induced by toxigenic Corynebacterium diphtheriae with two biotypes, namely intermedius (60.0%) and mitis (40.0%). There are six sequence types of bacteria with two main sequence types, ie, ST534 (46.4%) and ST377 (35.7%). The proportions of cases that had a fever and sore throat were 72.5% and 77.5%, respectively; however, the prevalence rates of the cases with pseudomembrane and bull neck were 100% and 47%, respectively. Most cases were administered a combination of penicillin or erythromycin with other antibiotics (40%), and 22.5% of the cases only received penicillin. Myocarditis was noticed in three fatal cases, and their relationship was statistically significant (P = 0.000). All five fatal cases (12.5% of cases) received diphtheria antitoxin (DAT) lately or had not received it yet. Conclusions: Toxigenic C. diphtheriae with two biotypes (namely mitis and intermedius) and two main sequence types (ie, ST534 and ST377) was the causative agent of diphtheria-confirmed cases from Jakarta and surrounding areas in 2017. It was also concluded that those fatal cases were correlated with myocarditis complications.

Diphtheria Antitoxin and Tales of Mercy in Northern Health Care

This article examines the history of diphtheria in the Yukon and the Mackenzie district of the Northwest Territories in the first half of the 20th century. This analysis follows the traces of this now largely forgotten disease and its treatment to illuminate the constraints – intrinsic and constructed – on the provision of health care commensurate with the expectations and needs of northern Indigenous peoples. While diphtheria was never the most serious infectious disease, nor a major cause of death compared with tuberculosis or influenza at this time, examining its history offers significant insight into the creation of medical and public health infrastructures in Canada’s northern territories, and the ways in which those infrastructures served, or failed to serve, different northern populations.

Diphtheria Antitoxin Administration, Outcomes, and Safety: Response to a Diphtheria Outbreak in Cox’s Bazar Bangladesh

Background Diphtheria has re-emerged over the past several years. There is a paucity of data on the administration and safety of diphtheria antitoxin (DAT), the standard treatment for diphtheria. The 2017-2018 outbreak among Rohingya refugees in Bangladesh was the largest in decades. We determined the outcomes of DAT-treated patients and describe the occurrence and risk factors associated with adverse reactions to DAT. Methods We conducted a retrospective study at the Médecins Sans Frontières Rubber Garden Diphtheria Treatment Center from December 2017-September 2018. Diphtheria was diagnosed based on the WHO clinical case criteria. High-acuity patients were eligible for DAT. Safety precautions were meticulously maintained. We calculated the presence of adverse events by age, duration of illness, and DAT dosage using bivariate comparisons. Results We treated 709 patients with DAT. Ninety-eight percent (n=696) recovered and were discharged. One-fourth (n=170) had at least one adverse reaction. Common reactions included cough (n=115, 16%), rash (n=66, 9%), and itching (n=37, 5%). Three percent (n=18) had severe hypersensitivity reactions. Five patients died during their DAT infusion or soon afterwards, but no deaths were attributed to DAT. Conclusions The outcomes for DAT-treated patients were excellent; mortality was less than 1%. Adverse reactions occurred in a quarter of all patients, but most reactions were mild and resolved quickly. DAT can be safely administered in a setting with basic critical care, provided that there is a continuous patient monitoring during the infusion, staff training on management of adverse effects, and attention to safety precautions.

RECOMMENDATION OF DIPHTHERIA ANTITOXIN TO DIFFERENT SUSPECTS DURING THE DIPHTHERIA OUTBREAKS,LUMAJANG DISTRICT IN 2018

The number of diphtheria suspects in Lumajang district was the second highest in East Java province during the diphtheria outbreaks in 2018. The number of diphtheria cases was more than 500% in 2018 compared to 2017. To give diphtheria antitoxin (DAT), the provincial diphtheria expert team consider various suspects’ characteristics for DAT recommendation as DAT supplies are limited. This case report aimed to explore and describe the relationship between diphtheria suspects’ characteristics, including age, gender, symptoms, immunization status, duration of disease, and contact status with other suspects according to the DAT recommendations from the expert team. This case report was descriptive and used a cross-sectional approach. It was conductedduring the diphtheria outbreaks and involved total samples of all suspects. Based on age, the majority of the suspects (92%)were under 19 years old. Suspects at this age were the target of an outbreak response immunization (ORI) program. Those who were not targetted to receive ORI (aged over 19 years) began to appear in November and mostly in December. The trend of non-ORI targetted age increased after the third round of ORI implementation. According to the report form parents, most suspects (46.7%) had complete immunization status, and only 6.7% of their immunization records were reported on growth chart cards. All suspects with positive diphtheria never had and know routine immunization records. The laboratory tests show only 5% were suspected with positive diphtheria with a cultural type of mitis toxigenic. As many as 32% of the total suspects were recommended for DAT treatment. The use of controlled DAT could save 1,640,000 iU. Keywords: Diphtheria, outbreak response immunization, diphtheria antitoxin.

Respiratory Illness Caused by Corynebacterium diphtheriae and C. ulcerans, and Use of Diphtheria Antitoxin in the United States, 1996–2018

Background Respiratory diphtheria is a toxin-mediated disease caused by Corynebacterium diphtheriae. Diphtheria-like illness, clinically indistinguishable from diphtheria, is caused by Corynebacterium ulcerans, a zoonotic bacterium that can also produce diphtheria toxin. In the United States, respiratory diphtheria is nationally notifiable: specimens from suspected cases are submitted to the Centers for Disease Control and Prevention (CDC) for species and toxin confirmation, and diphtheria antitoxin (DAT) is obtained from CDC for treatment. We summarize the epidemiology of respiratory diphtheria and diphtheria-like illness and describe DAT use during 1996–2018 in the United States. Methods We described respiratory diphtheria cases reported to the National Notifiable Diseases Surveillance System (NNDSS) and C. ulcerans-related diphtheria-like illness identified through specimen submissions to CDC during 1996–2018. We reviewed DAT requests from 1997 to 2018. Results From 1996 to 2018, 14 respiratory diphtheria cases were reported to NNDSS. Among these 14 cases, 1 was toxigenic and 3 were nontoxigenic C. diphtheriae by culture and Elek, 6 were culture-negative but polymerase chain reaction (PCR)-positive for diphtheria toxin gene, 1 was culture-positive without further testing, and the remaining 3 were either not tested or tested negative. Five cases of respiratory diphtheria-like illness caused by toxigenic C. ulcerans were identified. DAT was requested by healthcare providers for 151 suspected diphtheria cases between 1997 and 2018, with an average of 11 requests per year from 1997 to 2007, and 3 per year from 2008 to 2018. Conclusions Respiratory diphtheria remains rare in the United States, and requests for DAT have declined. Incidental identification of C. ulcerans-related diphtheria-like illness suggests surveillance of this condition might be warranted.