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.

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.

Fatal diphtheria myocarditis in a 3-year-old girl-related to late availability and administration of antitoxin?

Sporadic cases of diphtheria are very rare throughout Europe. A 3-year-old incompletely vaccinated girl was admitted with pharyngotonsillitis caused by diphtheria. On day 9 of her illness, renal and cardiac failure with a third-degree AV-block occurred. Unfortunately, she died within 36 h of admission to intensive care, despite pacemaker placement, the administration of antibiotics and diphtheria antitoxin. The delayed antitoxin administration 7 days after admission to hospital was related to a lack of availability and knowledge of its availability in Europe and this is likely to have contributed to the unfavourable outcome.

Characterization of serum anti-diphtheria antibody activity following administration of equine anti-toxin for suspected diphtheria.

There is a global shortage of equine-derived diphtheria anti-toxin (DAT) for diphtheria treatment. There are few existing data on serum antibody concentrations and neutralizing activity post-treatment to support development of new therapeutics. Antibody concentrations were quantified by ELISA and anti-toxin neutralizing activity by cytotoxicity assay in serum from 4 patients receiving DAT for suspected diphtheria. Using linear mixed effects modeling, estimated mean (SE) half-life was 78.2 (20.0) hours. Maximum serum neutralizing activity ranged from 28.42-38.64 AU/mL with an estimated mean AUC1-72 of 1396.7 (399.3) AU/mL*hr. These data provide a standard of comparison for development of novel anti-toxins to replace DAT.

Potency of a human monoclonal antibody to diphtheria toxin relative to equine diphtheria anti-toxin in a guinea pig intoxication model.

Prompt administration of anti-toxin reduces mortality following Corynebacterium diphtheriae infection. Current treatment relies upon equine diphtheria anti-toxin (DAT), with a 10% risk of serum sickness and rarely anaphylaxis. The global DAT supply is extremely limited; most manufacturers have ceased production. S315 is a neutralizing human IgG1 monoclonal antibody to diphtheria toxin that may provide a safe and effective alternative to equine DAT and address critical supply issues. To guide dose selection for IND-enabling pharmacology and toxicology studies, we dose-ranged S315 and DAT in a guinea pig model of diphtheria intoxication based on the NIH Minimum Requirements potency assay. Animals received a single injection of antibody premixed with toxin, were monitored for 30 days, and assigned a numeric score for clinical signs of disease. Animals receiving ≥ 27.5 µg of S315 or ≥ 1.75 IU of DAT survived whereas animals receiving ≤ 22.5 µg of S315 or ≤ 1.25 IU of DAT died, yielding a potency estimate of 17 µg S315/IU DAT (95% CI 16-21) for an endpoint of survival. Because some surviving animals exhibited transient limb weakness, likely a systemic sign of toxicity, DAT and S315 doses required to prevent hind limb paralysis were also determined, yielding a relative potency of 48 µg/IU (95% CI 38-59) for this alternate endpoint. To support advancement of S315 into clinical trials, potency estimates will be used to evaluate the efficacy of S315 versus DAT in an animal model with antibody administration after toxin exposure, more closely modeling anti-toxin therapy in humans.

[Comparative efficacy of homologous and heterologous biologicals against diphtheria].

AIM: Comparative assessment of efficacy of homologous and heterologous diphtheria antitoxins on the example of diphtheria intoxication. MATERIALS AND METHODS: Homologous hyperimmune sera were obtained through immunization of rabbits and guinea-pigs with diphtheria toxoid according to schedule. Immune rabbit sera contained 70 - 100 IU/mL of antitoxin antibodies and guinea-pig sera contained 60 - 80 IU/mL. Equine diphtheria antitoxin was used as a heterologous one. Measurement of antitoxin level using experimental animals is based on quantitative assessment of ability of studied sera to neutralize specific dermonecrotic effect of diphtheria toxin. RESULTS: Concentration of antitoxin in blood of different groups of guinea-pigs immunized 2 days earlier with either heterologous equine antitoxin or homologous antitoxin was 0.06 - 0.125. IU/mL. Animals from both groups were completely protected after administration of 5.64 LD50 of toxin. Alongside with it, 50 - 75% of animals which received homologous antitoxin were protected from higher doses of toxin, whereas all animals which received heterologous antitoxin died after administration of higher doses. After administration of identical doses of homologous antitoxin to rabbits its maximal concentration was observed on the next day, was stable up to 5 - 7 days after injection, decreased two-fold to 12th day and did not change further to 15 - 16 days after injection with subsequent another two-fold decrease to 30th day (then was stable for another 5 - 10 days). CONCLUSION: Administration of homologous antitoxin compared to heterologous analogue allows to prolong time of circulation of specific antitoxic antibodies in 3 - 4 times.

[Assessment of different regimens of diphtheria serotherapy].

AIM: Efficacy of different treatment regimens with equine diphtheria antitoxin (EDA) was assessed on clinical samples as well as in experiments on animals. MATERIALS AND METHODS: Protective properties and serum concentration kinetics of heterologous antibodies was studied on 12 rabbits and 51 guinea pigs after intramuscular injection of different doses of EDA, in serum samples from 26 patients, which received one intramuscular injection of EDA in various doses as well as in serum samples from 10 patients with diphtheria of different severity, which were treated with EDA in total course dose 100,000-1,500,000 IU. Antitoxin concentration in serum sample was measured with passive hemagglutination assay as well as Jensen toxin neutralization test on rabbits. RESULTS: Experiments on laboratory animals received EDA in dose 150 IU/kg showed high protective effect. For example, rabbits with antitoxin level 1.0-1.25 IU/ ml in serum 24 hours after injection of EDA were 50-250 times resistant to dermonecrotic effect of diphtheria toxin compared with rabbits not received EDA. Guinea pig with antitoxin level 0.5-2.0 IU/ ml in serum 2-48 hours after injection of EDA in dose 150 IU/kg were all protected against 35-50 LD50 of diphtheria toxin. After termination of EDA injection there was sharp decrease of antitoxin level and it was not detected in serum 7 days after. Increase of antitoxin level in serum of animals was not adequate to quantity of injected EDA. Study of serum samples from 26 patients received one intramuscular injection of different doses of EDA showed that doses of antitoxin from 20,000 to 30,000 IU resulted in its presence in serum in concentration 0.5-3.0 IU/ml whereas injection of 50,000 IU or 70,000-100,000 IU resulted in serum concentrations 1.25-10.0 IU/ ml and 2.5-20.0 IU/ml respectively. CONCLUSION: Relatively low doses of EDA provided relatively high level of protection against diphtheria toxin that should be taken into account during treatment of diphtheria patients.

Diphtheria: a case report.

OBJECTIVE: We report a case of diphtheria in an elderly patient, with a fatal outcome. METHOD: Case report and a review of the literature concerning the current recommended guidelines on detection of, and response to, diphtheria. RESULTS: Although still rare, cases of diphtheria are being reported with increasing frequency in the UK, possibly as a result of immigration and travel. A high index of suspicion, rapid detection of carriers, and instigation of treatment and vaccination are the mainstays of management. CONCLUSION: Diphtheria can mimic other forms of acute upper airway obstruction and can lead to a fatal outcome. Otorhinolaryngological surgeons need to consider this re-emergent disease as a potential diagnosis in patients with an unusual presentation of airway obstruction.

[Donor human antidiphtheritic immunoglobulin is an alternative to xenogeneic antidiphtheritic serum].

A new donor antidiphtheritic immunoglobulin produced in the Hematology and Transfusiology Institute of AMS of Ukraine and Donetsk transfusiology station is discussed in the article. The medication, antidiphtheritic horse serum had been used during the diphtheria epidemic, as a medication in Donetsk clinics. The medication meets requirements of State and International Standards and is registered in Ukraine.

Collaborative study for establishment of the European Pharmacopoeia BRP batch 1 for diphtheria toxin.

A stable liquid candidate Biological Reference Preparation (BRP) for diphtheria toxin was prepared in peptone buffer (nominal content of diphtheria toxin: 1 Lf/ml, 0.4 micro g/ml), filled in ampoules (filling volume: 1 ml) and characterised in a collaborative study. The toxin is to be used in the test "Absence of toxin and irreversibility of toxoid" as described in the current European Pharmacopoeia (Ph. Eur.) monograph Diphtheria Vaccine (Adsorbed) (2002:0443). Eleven laboratories assessed the specific activity of the preparation by in vivo and in vitro assays. The material is assumed to have satisfactory stability with a calculated predicted loss of activity of <1% per year at 4-8 degrees C. From the collaborative study, the specific activity was calculated as 77.6 (45-113) LD( 50)/ml (lethal challenge) and >75 000 Lr/Lf (intradermal challenge). The candidate BRP was successfully used in nine laboratories and confirmed suitable for use in the Vero cell test for "Absence of toxin and irreversibility of toxoid" as described in the Ph. Eur. monograph 2002:0443; i.e., concentrations of 5 x 10( -5) Lf/ml and below caused cytotoxic effects in the Vero cell test. Due to its liquid nature, the stability of the material will be monitored at regular intervals and preparation of a stable freeze-dried formulation will be considered for long-term use. Additional studies will be performed to confirm suitability of this BRP for other applications. The candidate BRP was adopted as the Ph. Eur. reference material for Diphtheria Toxin Batch 1 by the Ph. Eur. Commission at its session in March 2003.

The 2001 serological survey in the Czech Republic--diphtheria.

Diphtheria morbidity in the Czech part of former Czechoslovakia showed a continuous downward trend between 1946 and 1974. Afterwards, sporadic cases of diphtheria were reported in some years. Compulsory vaccination against diphtheria was started in 1946 with a monovaccine, later replaced by bivaccine DiTe. Since 1958, newborns have been vaccinated with DiTePe vaccine. As many as 98% to 100% of the population of age groups under 50 years likely to have been vaccinated have antibody levels > 0.01 lU/ml. About 83% to 88% of the older age groups who represent a naturally immunized population have antibodies as well. This immune status excludes the possibility that diphtheria could spread massively if accidentally imported into the Czech Republic.

[Mathematical model of the infection process in diphtheria for determining the therapeutic dose of antitoxic anti-diphtheria serum]. / Matematicheskaia model' infektsionnogo protsessa pri difterii dlia opredeleniia terapevticheskoi dozy antitoksicheskoi protivodifteriinoi syvorotki.

It is known that administration of horse serum against diphtheria toxin can cause autoimmune and allergic complications. Therefore it is important for improvement of serotherapy to develop methods of prediction of disease course and quantity of diphtheria toxin and antitoxic antibodies in a serum. We have developed the mathematical model of diphtheria infection, which consists of six differential equations describing dynamics of diphtheria toxin and antitoxic antibodies in a serum, quantity of infection agent and macrophages in a site of inflammation. This mathematical model allows to predict the course of infectious process, the level of diphtheria toxin and antitoxic antibodies in the sera of people with diphtheria and to calculate the individual therapeutic dose of antitoxic serum for each patient.

[The clinical manifestations, diagnosis and treatment of diphtheria in adults]. / Klinicheskie proiavleniia, diagnostika i lechenie difterii u vzroslykh.

Diphtheria morbidity among adult population of Moscow is growing. The tests of different modes and schemes of heterogeneous antidiphtheria serum administration have found out that the highest efficacy of serotherapy was achieved with a single intravenous dose. Another treatment of diphtheria is hemosorption. Widely used in present-day clinical practice hemosorbents provide adequate elimination of the toxin from plasma. The authors analyse the present situation in clinical symptoms, complications, lethality of diphtheria basing on the data provided by S. P. Botkin's Hospital.

Difteria faríngea: revisión de 307 enfermos / Pharyngeal diphteria: review of 307 patients

Si bien en la última década, la morbimortalidad de la difteria en Chile ha disminuído considerablemente, desde 1984 se ha observado un aumento, como consecuencia de brotes geográficamente limitados. Ha parecido interesante comunicar el análisis de 307 enfermos, bacteriológicamente confirmados, en el Hospital de Enfermedades Infecciosas de Santiago de Chile, entre enero 1972 y diciembre 1984; 174 mujeres (56,6 por ciento) y 133 hombres (43,4 por ciento), con edades entre 5 y 14 años, en el 54,5 por ciento. Un 26 por ciento tuvo mas de 25 años, lo que estaría de acuerdo al desplazamiento paulatino de la difteria a edades mayores. La mitad presentó formas graves. El 84,7 por ciento ingresó dentro de los primeros 4 días. Recibieron antitoxina y la mayoría penicilina sódica, junto con corticoides en los cuadros severos. se comprobó complicaciones únicas o asociadas: miocarditis en 78 (29 por ciento) de 269 enfermos con electrocardiograma; parálisis, mas frecuente velopalatina (22,5 por ciento); nefritis, en 23 (14,5 por ciento) de 159 con uremia y/o creatinemia mas examen de orina. Las complicaciones fueron casi excepcionales en la forma común. La letalidad global fue de 5,5 por ciento ya que no hubo fallecidos con forma leve. En cambio, aquella alcanzó a 36,5 por ciento en la maligna, estando determinada por el daño miocárdico y renal

[Seroconversion in juvenile patients and adults after diphtheria immunization]. / Serokonversion nach Diphtherieschutzimpfung bei Jugendlichen und Erwachsenen.

A total of 155 persons of the Hamburg hospital personnel aged between 15 and 64 years were immunised against diphtheria. Out of 120 prevaccination seronegative persons (including very low diphtheria antitoxin titres) 92 (76.7%) reacted with seroconversion above the diphtheria protection level after the adult dosage of 7.5 IU diphtheria toxoid. Good results were still obtained with a 2.5 IU dosage. The conversion factor of 210 in the age group of 55 to 64 year old persons was sevenfold higher than in the 15 to 24 year old group. Local reactions of the mainly slight nature were seen after vaccination in 20.8%, only immunised person showed a slight increase of temperature. It is recommended to offer reimmunisation with a 7.5 IU dosage before leaving school. Selective immunisation of certain professional groups, such as hospital personnel, should be performed according to age and history, either with 7.5 or 2.5 IU of diphtheria toxoid.