A case of fulminant respiratory diphtheria in a 24-year-old Afghan refugee in Austria in May 2022: a case report.

PURPOSE: Raising awareness of respiratory diphtheria and for the importance of early antitoxin administration. METHODS: Report of a case of fulminant, imported respiratory diphtheria in an otherwise healthy 24-year-old Afghan refugee in Austria in May 2022. RESULT: This was the first case of respiratory diphtheria in Austria since 1993. Diphtheria antitoxin was administered at an already progressed disease stage. This delay contributed to a fulminant disease course with multiorgan failure and death. CONCLUSION: In high-income countries with low case numbers, awareness of respiratory diphtheria and for the importance of early antitoxin administration must be raised.

Collaborative study for the calibration of a replacement International Standard for Diphtheria Antitoxin Equine.

The International Standard for Diphtheria Antitoxin Equine is essential for the standardisation of assays used to determine the potency of therapeutic diphtheria antitoxin products produced from equine serum. This paper describes the production and characterization of the 2nd International Standard for Diphtheria Antitoxin Equine and its calibration in International Units. Calibration was performed by toxin neutralization test in vivo and in vitro (Vero cell assay), and potency was expressed relative to the 1st International Standard to ensure continuity of the International Unit. The candidate standard (NIBSC product code 18/180) was assigned a unitage of 57 IU/ampoule based on results from 14 laboratories in 9 different countries and was established by the World Health Organisation Expert Committee on Biological Standardization in 2021.

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.

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.

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 World Health Organization 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; 98% (n = 696) recovered and were discharged. One-fourth (n = 170) had at least 1 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: Outcomes for DAT-treated patients were excellent; mortality was <1%. Adverse reactions occurred in one-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 there is continuous patient monitoring during the infusion, staff training on management of adverse effects, and attention to safety precautions.

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, and failed to serve, different northern populations.

Induction of antibody responses in mice immunized intranasally with Type I interferon as adjuvant and synergistic effect of chitosan.

Type I IFNs are a range of host-derived molecules with adjuvant potential; they have been used for many years in the treatment of cancer and viral hepatitis. Therefore, the safety of IFNs for human use has been established. In this study, we evaluated the mucosal adjuvanticity of IFN-ß administered intranasally to mice with diphtheria toxoid, and suggested a method to improve its adjuvanticity. When IFN-ß alone was used as a mucosal adjuvant, no clear results were obtained. However, simultaneous administration of IFN-ß and chitosan resulted in an enhancement of the specific serum immunoglobulin G (IgG) and IgA antibody responses, the mucosal IgA antibody response, and antitoxin titers. Furthermore, the intranasal administration of IFN-α alone resulted in a greater increase in antibody titer than IFN-ß, and a synergistic effect with chitosan was also observed. These findings suggest that intranasal administration of chitosan and Type I IFNs may display an effective synergistic mucosal adjuvant activity.

Diphtheria in Children in Northern Haiti.

Infection with Corynebacterium diphtheriae persists in Haiti. Twenty-six children with clinically severe respiratory diphtheria presented to a hospital in northern Haiti during a 3-year period beginning in early 2015. The mortality rate was 50%. Partial or absent vaccinations as well as delayed and limited care contributed to mortality. This cohort offer insights into the multiple challenges involved in preventing and caring for children with diphtheria in resource-limited settings.

Microbe Profile: Corynebacterium diphtheriae - an old foe always ready to seize opportunity.

Corynebacterium diphtheriae is a globally important Gram-positive aerobic Actinobacterium capable of causing the toxin-mediated disease, diphtheria. Diphtheria was a major cause of childhood mortality prior to the introduction of the toxoid vaccine, yet it is capable of rapid resurgence following the breakdown of healthcare provision, vaccination or displacement of people. The mechanism and treatment of toxin-mediated disease is well understood, however there are key gaps in our knowledge on the basic biology of C. diphtheriae particularly relating to host colonisation, the nature of asymptomatic carriage, population genomics and host adaptation.

A case of respiratory toxigenic diphtheria: contact tracing results and considerations following a 30-year disease-free interval, Catalonia, Spain, 2015.

In May 2015, following a 30-year diphtheria-free interval in Catalonia, an unvaccinated 6-year-old child was diagnosed with diphtheria caused by toxigenic Corynebacterium diphtheriae. After a difficult search for equine-derived diphtheria antitoxin (DAT), the child received the DAT 4 days later but died at the end of June. Two hundred and seventeen contacts were identified in relation to the index case, and their vaccination statuses were analysed, updated and completed. Of these, 140 contacts underwent physical examination and throat swabs were taken from them for analysis. Results were positive for toxigenic C. diphtheriae in 10 contacts; nine were asymptomatic vaccinated children who had been in contact with the index case and one was a parent of one of the nine children. Active surveillance of the 217 contacts was initiated by healthcare workers from hospitals and primary healthcare centres, together with public health epidemiological support. Lack of availability of DAT was an issue in our case. Such lack could be circumvented by the implementation of an international fast-track procedure to obtain it in a timely manner. Maintaining primary vaccination coverage for children and increasing booster-dose immunisation against diphtheria in the adult population is of key importance.

Adult diphtheria in Malaysia: A case report.

In November 2016, a 28-year-old Malay man presented to the emergency department in respiratory distress, with a history of fever and sore throat. A clinical diagnosis of acute diphtheria was made and the patient was isolated and ventilated in the intensive care unit, and received diphtheria antitoxin and intravenous antibiotics. Initial laboratory findings failed to confirm diphtheria, leading to discontinuation of antibiotics and quarantine. Public health measures were reinstated after a reference laboratory cultured Corynebacterium diphtheriae. Although there was no contact with ill persons, investigation revealed incomplete immunisation history, and injection of high dose steroids prior to onset of symptoms.

Postbooster Antibodies from Humans as Source of Diphtheria Antitoxin.

Diphtheria antitoxin for therapeutic use is in limited supply. A potential source might be affinity-purified antibodies originally derived from plasma of adults who received a booster dose of a vaccine containing diphtheria toxoid. These antibodies might be useful for treating even severe cases of diphtheria.

Toxigenic Corynebacterium ulcerans isolated from a hunting dog and its diphtheria toxin antibody titer.

Toxigenic Corynebacterium ulcerans is a zoonotic pathogen that produces diphtheria toxin and causes a diphtheria-like illness in humans. The organism is known to infect and circulate among dogs, which can then transmit it to humans. Furthermore, previous studies have found that C. ulcerans is carried by wild animals, including game animals. In the present study, we tested hunting and companion dogs for the presence of toxigenic C. ulcerans and succeeded in isolating the bacterium from a hunting dog. Moreover, several hunting dogs had serum diphtheria antitoxin titers that were higher than the titers required for protection in humans, suggesting a history of exposure to toxigenic Corynebacterium strains. Notably, ribotyping, pulsed-field gel electrophoresis and tox gene sequencing demonstrated that the isolate from the hunting dog clustered with previously characterized C. ulcerans strains isolated from wild animals, as opposed to groups of isolates from humans and companion dogs. Interestingly, the wild animal cluster also contains an isolate from an outdoor breeding dog, which could have formed a bridge between isolates from wild animals and those from companion dogs. The results presented herein provide insight into the mechanism by which the zoonotic pathogen C. ulcerans circulates among wild animals, hunting and companion dogs, and humans.

Respiratory diphtheria in an asylum seeker from Afghanistan arriving to Finland via Sweden, December 2015.

In December 2015, an asylum seeker originating from Afghanistan was diagnosed with respiratory diphtheria in Finland. He arrived in Finland from Sweden where he had already been clinically suspected and tested for diphtheria. Corynebacterium diphtheriae was confirmed in Sweden and shown to be genotypically and phenotypically toxigenic. The event highlights the importance of early case detection, rapid communication within the country and internationally as well as preparedness plans of diphtheria antitoxin availability.

Early Developments in the Regulation of Biologics.

This article is a history of the policy positions and legal interpretations adopted by the Public Health Service (PHS) under the 1902 Biologics Control Act. PHS generally interpreted the scope of the Act narrowly because it lacked authority to deny marketing licenses for ineffective biologics and wanted to minimize the number of worthless drugs with the imprimatur of a governmental license. In addition, PHS implemented important regulatory strategies not expressly authorized by the Act.

What you don't know about vaccines can hurt you.

As physicians, we've all learned in detail about the science behind vaccinations, but I suspect few of us have been taught about the history of vaccinations. Sure, we all know that Dr. Jonas Salk developed the poliovirus vaccine, but I wasn't aware that he inoculated himself, his wife, and his three children with his then experimental vaccine. When our editorial committee decided to focus on vaccinations as our theme for this month's Greene County Medical Society's Journal, I perused the internet for interesting topics. I came across a fascinating website, historyofvaccines.org; this website is a project of the College of Physicians of Philadelphia, touted as being the oldest professional medical organization in the United States. I credit the majority of the information in this article to the above website and the rest to the National Institutes of Health (nih.gov) website; I trust that the information is valid and true, based on the agencies behind these websites. Below are some interesting tidbits about vaccine preventable diseases that I found noteworthy to pass on to our readers.

Access to diphtheria antitoxin for therapy and diagnostics.

The most effective treatment for diphtheria is swift administration of diphtheria antitoxin (DAT) with conjunct antibiotic therapy. DAT is an equine immunoglobulin preparation and listed among the World Health Organization Essential Medicines. Essential Medicines should be available in functioning health systems at all times in adequate amounts, in appropriate dosage forms, with assured quality, and at prices individuals and the community can afford. However, DAT is in scarce supply and frequently unavailable to patients because of discontinued production in several countries, low economic viability, and high regulatory requirements for the safe manufacture of blood-derived products. DAT is also a cornerstone of diphtheria diagnostics but several diagnostic reference laboratories across the European Union (EU) and elsewhere routinely face problems in sourcing DAT for toxigenicity testing. Overall, global access to DAT for both therapeutic and diagnostic applications seems inadequate. Therefore--besides efforts to improve the current supply of DAT--accelerated research and development of alternatives including monoclonal antibodies for therapy and molecular-based methods for diagnostics are required. Given the rarity of the disease, it would be useful to organise a small stockpile centrally for all EU countries and to maintain an inventory of DAT availability within and between countries.

[Throat disease in the periphery of Europe: the introduction of diphteria antitoxin in Romsdal county]. / Halsesyke i Europas utkant--da difteriantitoksinet kom til Romsdals amt.

Diphteria played a key role in establishing the bacteriological model for explaining infectious disease. This understanding of bacteriological factors spurred research that culminated in the development of diphteria antitoxin, the first effective therapeutic cure for an epidemiological disease. Prior to the introduction of antitoxin, isolation and disinfection were regarded as the key defences against diphteria. The opportunity to combine antitoxin therapy with existing methods for combatting the disease was a key factor for the rapid spread of the antitoxin. Diphteria antitoxin was first used in Romsdal county in 1895. Initially the serum had to be ordered from manufacturers abroad, which restricted its application in the district. Few available doctors and long transport routes were reasons that prevented the antitoxin from reaching its full potential. Industrial manufacturing methods were an obstacle to serum production in peripheral areas. In Norway, production of serum gradually got underway in Kristiania, which was one factor that caused mortality from diphteria to decline faster there than in other parts of the country. In this article we will elucidate the relationship between the centre and the periphery in the spread of medical advances by studying the implementation of diphteria antitoxin in Romsdal county.