Real-time analysis of the diphtheria outbreak in forcibly displaced Myanmar nationals in Bangladesh.

BACKGROUND: Between August and December 2017, more than 625,000 Rohingya from Myanmar fled into Bangladesh, settling in informal makeshift camps in Cox's Bazar district and joining 212,000 Rohingya already present. In early November, a diphtheria outbreak hit the camps, with 440 reported cases during the first month. A rise in cases during early December led to a collaboration between teams from Médecins sans Frontières-who were running a provisional diphtheria treatment centre-and the London School of Hygiene and Tropical Medicine with the goal to use transmission dynamic models to forecast the potential scale of the outbreak and the resulting resource needs. METHODS: We first adjusted for delays between symptom onset and case presentation using the observed distribution of reporting delays from previously reported cases. We then fit a compartmental transmission model to the adjusted incidence stratified by age group and location. Model forecasts with a lead time of 2 weeks were issued on 12, 20, 26 and 30 December and communicated to decision-makers. RESULTS: The first forecast estimated that the outbreak would peak on 19 December in Balukhali camp with 303 (95% posterior predictive interval 122-599) cases and would continue to grow in Kutupalong camp, requiring a bed capacity of 316 (95% posterior predictive interval (PPI) 197-499). On 19 December, a total of 54 cases were reported, lower than forecasted. Subsequent forecasts were more accurate: on 20 December, we predicted a total of 912 cases (95% PPI 367-2183) and 136 (95% PPI 55-327) hospitalizations until the end of the year, with 616 cases actually reported during this period. CONCLUSIONS: Real-time modelling enabled feedback of key information about the potential scale of the epidemic, resource needs and mechanisms of transmission to decision-makers at a time when this information was largely unknown. By 20 December, the model generated reliable forecasts and helped support decision-making on operational aspects of the outbreak response, such as hospital bed and staff needs, and with advocacy for control measures. Although modelling is only one component of the evidence base for decision-making in outbreak situations, suitable analysis and forecasting techniques can be used to gain insights into an ongoing outbreak.

Clinical Serum Therapy: Benefits, Cautions, and Potential Applications.

Blood serum from immunized humans or animals (e.g., horses) contains relevant antibodies and has been used as serum therapy to treat many diseases or envenomation events. The effectiveness of blood serum was initially discovered in 1890 when Kitasato and von Behring observed the effectiveness of this type of therapy against diphtheria and tetanus. Serum therapies played an important role in the advancement of modern medicine prior to the development of penicillin and steroids. At present, several types of serum therapy remain in clinical use. However, some physicians have a limited understanding of the nature and the benefits of serum therapy and the factors that require particular attention. In this review, we set out to clarify the benefits, cautions, and potential applications of serum therapy in the context of conditions such as gas gangrene, diphtheria, botulism, and tetanus and bites from three snake species (mamushi, habu, and yamakagashi) and the redback spider. It is hoped that this review will help clinicians to learn about clinical serum therapies and become familiar with their applications.

Sudden death of a child due to respiratory diphtheria.

A four-year-old girl presented to the emergency department with respiratory distress. Death occurred despite attempted resuscitation. The illness was not clinically diagnosed. Her father revealed that she had a fever and sore throat for the last four days and was not immunised for diphtheria. Characteristic gross and microscopic pathology of respiratory diphtheria and microbiological findings were observed. The cause of death was acute respiratory failure consequent upon upper airway obstruction from diphtheria. Forensic pathologists should remember that the diphtheria cases can cause sudden death especially in developing countries.

Characterization of DIP0733, a multi-functional virulence factor of Corynebacterium diphtheriae.

Corynebacterium diphtheriae is typically recognized as an extracellular pathogen. However, a number of studies revealed its ability to invade epithelial cells, indicating a more complex pathogen-host interaction. The molecular mechanisms controlling and facilitating internalization of Cor. diphtheriae are poorly understood. In this study, we investigated the role of DIP0733 as virulence factor to elucidate how it contributes to the process of pathogen-host cell interaction. Based on in vitro experiments, it was suggested recently that the DIP0733 protein might be involved in adhesion, invasion of epithelial cells and induction of apoptosis. A corresponding Cor. diphtheriae mutant strain generated in this study was attenuated in its ability to colonize and kill the host in a Caenorhabditis elegans infection model system. Furthermore, the mutant showed an altered adhesion pattern and a drastically reduced ability to adhere and invade epithelial cells. Subsequent experiments showed an influence of DIP0733 on binding of Cor. diphtheriae to extracellular matrix proteins such as collagen and fibronectin. Furthermore, based on its fibrinogen-binding activity, DIP0733 may play a role in avoiding recognition of Cor. diphtheriae by the immune system. In summary, our findings support the idea that DIP0733 is a multi-functional virulence factor of Cor. diphtheriae.

Corynebacterium diphtheriae and the returned tropical traveler.

BACKGROUND: In Western countries, nontoxigenic Corynebacterium diphtheriae is known to cause skin and soft tissue infections (SSIs), upper respiratory tract infections, and occasionally invasive disease. Its role as a skin pathogen in returned travelers from tropical destinations where the organism is endemic is often forgotten. A retrospective analysis of a large Australian private pathology laboratory's experience with C. diphtheriae was performed to identify how frequently overseas travel was associated with C. diptheriae infection/colonization. METHODS: All C. diphtheriae isolates cultured from 2002 to 2012 were reviewed. Recorded clinical information regarding recent travel, country, and cause of infection was assessed. Antibiotic susceptibility was verified on all isolates. RESULTS: In all there were 72 patients who had C. diphtheriae isolated on clinical specimens, and information about prior travel was available for 63. Seventy percent of these were healthy individuals with an SSI and history of recent travel to a tropical nation. Ninety-seven percent had associated copathogens. Two isolates were penicillin resistant. There was uniform susceptibility to cephalothin, clindamycin, erythromycin, and vancomycin, with 14% resistance to trimethoprim/sulfamethoxazole and 4% resistance to tetracycline. Only one isolate was a toxigenic strain. CONCLUSION: The majority of C. diphtheriae isolated were from SSIs in otherwise healthy travelers returning from tropical destinations, rather than classical risk groups. Clinicians and laboratories need to be aware of this potential source of C. diphtheriae infection due to rare toxigenic strains.

Toxigenic Corynebacterium ulcerans infection in a veterinary student in London, United Kingdom, May 2010.

We report on a case of toxigenic Corynebacterium ulcerans infection in a fully immunised veterinary student, investigated in London, United Kingdom, in May 2010. There was no ongoing transmission in human contacts. Possible animal sources were identified.

Prognostic significance of electrocardiographic abnormalities in diphtheritic myocarditis after hospital discharge: a long-term follow-up study.

OBJECTIVE: We aimed to investigate the long-term cardiac mortality and the relationship between cardiac mortality and electrocardiographic abnormalities in patients with diphtheritic myocarditis who survived after hospital discharge. MATERIALS AND METHODS: Between 1991 and 1996, 32 patients (all males, mean age 21.00 +/- 3.77 years) surviving diphtheritic myocarditis were included in the study and they were followed up for an average of 16.3 months (range 10.3-26.8 months) after hospital discharge. Clinical evaluation, ECG, and echocardiography were performed on admission, daily while in hospital and at the time of discharge. ECG changes were permanent during the follow-up period. The causes of death of the patients during follow-up period were inferred from the death records of the patients and talking to the people witnessing cardiac arrest. RESULTS: We observed that the patients with left bundle branch block (LBBB) and T wave inversion at hospital discharge had lower survival rates than that of the patients without these ECG changes in the long term. Although univariate Cox regression analysis identified LBBB (P = 0.001) and T wave inversion (P = 0.014) as the predictors of survival, only LBBB was an independent predictor of survival in multivariate Cox regression analysis. Adjusted hazard ratio was calculated as 13.67 for LBBB (P = 0.001; CI = 2.81-66.28). CONCLUSION: Diphtheritic myocarditis does not only demonstrate a malignant clinical course during acute phase of the disease, but also during the long-term follow-up period, especially in patients with LBBB and T wave inversion. Besides, T wave inversion and LBBB can help us to predict survival rate of the patients in long term. Moreover, LBBB is an independent predictor of long-term survival in diphtheritic myocarditis.

Diphtheria with polyneuropathy in a closed community despite receiving recent booster vaccination.

INTRODUCTION AND METHODS: We report 20 patients aged 18-24 years from Latvia with diphtheritic polyneuropathy. All lived in a closed community and 80% were known to have been fully vaccinated against diphtheria until at least 14 years old. Diphtheria antitoxin had been administered within 3 days of the onset of upper respiratory tract infection in 16 patients and 15 received antibiotics. RESULTS: Neurological symptoms developed after a median of 43 days (range 35-58) compared to only 10 days in previous studies of unvaccinated patients. All showed evidence of mild limb polyneuropathy with electrophysiological evidence of polyneuropathy. Only 30% showed early bulbar abnormalities compared to the usual rate of over 95% in diphtheritic polyneuropathy. However, 45% had later bulbar deterioration coinciding with the limb polyneuropathy. CONCLUSIONS: These patients show that an attenuated form of polyneuropathy of later onset, with less prominent early bulbar features, can occur in patients vaccinated against diphtheria according to schedule but living in a closed community in a country where diphtheria remains endemic.

Clinical features and predictors of diphtheritic cardiomyopathy in Vietnamese children.

BACKGROUND: Despite the availability of antitoxin and antibiotics, the mortality rate for diphtheria remains high, mostly because of cardiac complications. METHODS: During 1 year, 154 Vietnamese children with diphtheria admitted to a referral hospital were studied prospectively with clinical examination, including a simple pseudomembrane score, 12-lead and 24-hour electrocardiography, measurement of serum cardiac enzyme levels, and estimation of troponin T levels. RESULTS: Thirteen children had diphtheritic cardiomyopathy on admission, and 19 developed it subsequently. Twelve children (8%) died. The combination of pseudomembrane score of >2 and bull neck predicted the development of diphtheritic cardiomyopathy, with a positive predictive value of 83% and a negative predictive value of 93%. Administration of 24-hour electrocardiography on admission improved the ability to predict diphtheritic cardiomyopathy by 57%. Fatal outcome was best predicted by the combination of myocarditis on admission and a pseudomembrane score of >2. Of the cardiac enzyme levels measured, an elevated aspartate aminotransferase level was the best predictor. The presence of troponin T identified additional children with subclinical cardiac damage. CONCLUSIONS: The development of diphtheritic cardiomyopathy can be predicted by means of simple measures.

Electrocardiographic abnormalities in patients with diphtheria: a prospective study.

PURPOSE: To determine the incidence of and risk factors for electrocardiographic (ECG) abnormalities in adults with diphtheria. METHODS: A prospective study was conducted involving 122 adult patients with respiratory tract diphtheria. Diphtheria was confirmed by isolation of a toxin-producing strain of Corynebacterium diphtheriae. Patients had serial clinical evaluations and ECGs for a minimum of 21 days. RESULTS: Cardiac involvement was detected in 25 (28%) of 88 evaluable patients, with a median time from symptom onset to an abnormal ECG of 9 days (range, 4 to 24 days). In a logistic regression analysis, age (odds ratio [OR] = 4.1; 95% confidence interval [CI]: 1.6 to 11.0), shared accommodation (OR = 2.9; 95% CI: 1.0 to 8.6), fever (OR = 4.2; 95% CI: 1.1 to 16.6), and extensive respiratory tract infection with subcutaneous edema (OR = 7.0; 95% CI: 1.2 to 42.2) were independent risk factors for cardiac involvement. CONCLUSION: Cardiac involvement is a common complication of respiratory tract infection with C. diphtheriae, and occurs more often among older patients, those with lower socioeconomic status, and those with severe respiratory tract involvement.

[Clinical and structural parallels in changes of the myocardial conduction system in diphtheria patients]. / Klinicheskie i strukturnye paralleli izmenenii provodiashcheisistemy serdtsa i miokarda u bol'nykh difteriei.

AIM: Comparison of the results of clinical device investigations of the heart with morphological autopsy evidence in diphtheria. MATERIAL AND METHODS: Hearts of 309 patients with diphtheria aged 25 to 80 years and 60 hearts of patients who died of diphtheria were investigated using ECG, echo-CG, doppler echo-CG, Holter ECG monitoring, biochemical tests of blood. Structural study of cardiac conduction included examination of the sinus-atrial node, atrioventricular node and bundle regarding the adjacent myocardium. RESULTS: Variants of structural-functional state of the myocardium and conduction system are explained by variability of the pathological processes which arose due to individual features of the conduction system structure and location, relationships with the myocardium. In acute diphtheria (day 1-10) dystrophic, necrobiotic and vascular disorders prevailed followed on days 11-30 by inflammation ending in myocardiosclerosis. Nodes and bundles of the conduction system are affected less frequently than the myocardium. CONCLUSION: A correlation exists between structural state of the cardiac conduction system and variants of clinical affection of the heart in diphtheria.

Infection of the skin caused by Corynebacterium ulcerans and mimicking classical cutaneous diphtheria.

Extrapharyngeal infections caused by Corynebacterium ulcerans have rarely been reported previously, and diphtheria toxin production has usually not been addressed. This case demonstrates that strains of C. ulcerans that produce diphtheria toxin can cause infections of the skin that completely mimic typical cutaneous diphtheria, thereby potentially providing a source of bacteria capable of causing life-threatening diseases in the patient's environment. Therefore, it is recommended to screen wound swabs for coryneform bacteria, identify all isolates, carefully assess possible toxin production, and send questionable strains to a specialist or a reference laboratory.

[Morphological characteristics of heart conduction system in diphtheria]. / Morfologicheskie izmeneniia provodiashchei sistemy srdtsa pri difterii.

Heart conductive system (HCS) including the sinoatrial node (SAN), atrioventricular node (AVN), AV bundle (AVB) and its left and right parts was studied histologically. It is shown that different portions of HCS are damaged in diphtheria with different frequency and intensity, the frequency depending on the depth of their location. Left part of AVB is affected most frequently, followed by the right part of AVB, AVB, AVN and the least frequently SAN.

[Clinical and prognostic significance of disturbed global and regional contractility of left ventricle in diphtheria myocarditis]. / Klinicheskoe i prognosticheskoe znachenie narushenii global'noi i regional'noi sokratimosti levogo zheludochka pri difteriinykh miokarditakh.

Examination of 159 diphtheria patients diagnosed myocarditis in 64 of them. The latter were divided into 3 groups: with mild, moderate and severe myocarditis. The patients with and without diphtheria have undergone two-dimensional echocardiography with estimation of the asinergia index (AI) and left ventricular (LV) ejection fraction. Pronounced systolic dysfunction was revealed only in severe diphtheric myocarditis (DM). AI rose in moderate and severe DM. By the degree of AI elevation it can be judged about myocarditis severity and the disease prognosis. Regional LV contractility and LV systolic dysfunction were correlated. A group of patients with severe DM was identified who had a high risk of death in akinesia of LV segments (IA > 2) and lowering of LV ejection fraction below 35%.

Diphtheritic polyneuropathy: a clinical study and comparison with Guillain-Barré syndrome.

OBJECTIVES AND METHODS: Clinical features of 50 adults with diphtheritic polyneuropathy (DP) were studied in Riga, Latvia and compared with 21 patients with Guillain-Barré syndrome (GBS). RESULTS: Neurological complications occurred in 15% of patients admitted to hospital with diphtheria and usually after severe pharyngeal infection. Bulbar dysfunction occurred in 98% of patients with DP and only 10% of patients with GBS. Limb weakness was mild or absent in 30% of patients with DP. Ventilation dependent respiratory failure occurred in 20% of patients with DP. The first symptoms of DP occurred 2-50 days after the onset of local diphtheria infection. Neurological deterioration in DP continued for a median of 49 (range 15-83) days and improvement started 73 (range 20-115) days after onset. In 66% of patients with DP, the neuropathy was biphasic with a secondary worsening after 40 days. By contrast patients with GBS worsened for only 10 days on average (range 2-28 days) and improved after 21 (range 4-49) days. Eight patients with DP died, four from severe cardiomyopathy and four from multiple diphtheritic organ failure. Prolonged distal motor latencies (DMLs) were common to both DP and GBS, and more pronounced than motor conduction slowing. Limb symptoms continued after 1 year in 80% of the patients with DP, 6% were unable to walk independently, but independent respiratory and bulbar function had returned in all survivors. By comparison no patients with GBS died and none were severely disabled after 1 year. No death, in patients with DP occurred after antitoxin on days 1 or 2 after onset of diphtheria symptoms, whereas identical rates of death and peak severity of DP were seen both in those who received antitoxin on days 3-6 and those who did not receive it at all. CONCLUSION: Diphtheric polyneuropathy is much more likely than GBS to have a bulbar onset, to lead to respiratory failure, to evolve more slowly, to take a biphasic course, and to cause death or long term disability. Antitoxin seems ineffective if administered after the second day of diphtheritic symptoms.

[Diphtheria and infections caused by Corynebacterium diphtheriae in 1997]. / La diphtérie et les infections liées à Corynebacterium diphtheriae en 1997.

INTRODUCTION: Diphtheria is a reemerging disease. Two epidemics recently occurred in Algeria and Independent States Community, not so far from Europe. Imported cases were diagnosed in contiguous European countries. This review focuses on the data obtained from these epidemics, with particular emphasis on new clinical forms of Corynebacterium diphtheriae infections. CURRENTS KNOWLEDGE AND KEY POINTS: Sore throat with membranes is no longer the only clinical feature of diphtheria. However, patients' management is identical, with combination of antibiotics, injection of specific antisera, and immunization of patients' close contacts and relatives. French and American sero-epidemiological studies showed that antibody levels does not provide protection, particularly in the elderly. Adult populations would therefore be at risk every 10 years. Recent advances in molecular biology led to the development of gene amplification with polymerase chain reaction, that may be used for the detection of the toxin gene. They also promoted epidemiological surveys of circulating strains via ribotyping. Although this technic evidenced predominant strains in the various countries, genotypes encountered during an epidemics may differ. Besides diphtheria which has apparently been eradicated in France, systemic infections with non-toxigenic strains of C diphtheriae, such as endocarditis, septicemia and arthritis, are evenly diagnosed. FUTURE PROSPECTS AND PROJECTS: A French national reference center for C diphtheriae has been recently created. This center collects most of the strains isolated in France, clinical data and assesses the toxigenicity of bacteria, allowing strict epidemiological survey.

Penicillin vs. erythromycin in the treatment of diphtheria.

In an open-label, randomized trial, 44 Vietnamese children with diphtheria were given penicillin therapy (intramuscular benzylpenicillin, 50,000 U/[kg.d] for 5 days and then oral penicillin, 50 mg/[kg.d] for 5 days), and 42 were given erythromycin therapy (50 mg/[kg.d] orally for 10 days). There were no differences in times to membrane clearance or bacteriologic clearance, but median times to fever clearance were 27 hours (95% confidence interval [CI], 19-30; range, 0-124 hours) for penicillin recipients and 46 hours (95% CI, 34-54; range, 0-148 hours) for erythromycin recipients (P = .0004). In the penicillin group, acute treatment failed for one patient, and one patient relapsed. Three patients in the penicillin group developed diphtheritic myocarditis as evidenced by abnormal electrocardiograms. Erythromycin did not cause prolongation of the QT interval corrected for heart rate. Cultures of specimens from 15 patients (17.4%) were positive for toxigenic Corynebacterium diphtheriae. All isolates were susceptible to penicillin, but for isolates (27%), all of which were from patients who received penicillin treatment, were resistant to erythromycin (minimum inhibitory concentrations, > 64 mg/L). Penicillin is recommended as first-line treatment for diphtheria in Vietnam.