Use Of Diphtheria Antitoxin Research Articles

A Good Time to Be Born

A Good Time to Be Born

Production of IgY polyclonal antibody against diphtheria toxin and evaluation of its neutralization effect by Vero cell assay

BackgroundDiphtheria is a bacterial disease which is caused by Corynebacterium diphtheriae. The symptoms are due to the diphtheria toxin produced by the bacteria. Antibiotic therapy and the use of diphtheria antitoxin is a recommended strategy to control diphtheria. Although mammalian antibodies are used to treat patients, IgY antibody has advantages over mammalian ones, including cost-effectiveness and production through non-invasive means. Moreover, in contrast to mammalian antibodies, IgY does not bind to the rheumatoid factor and does not activate the complement system. The objective of this study was to evaluate the in vitro neutralizing effect of IgY against diphtheria toxin.ResultsAnti-DT IgY was produced by immunization of the laying white leghorn chickens. Indirect enzyme-linked immunosorbent assay revealed successful immunization of the animals, and the IgY was purified with a purity of 93% via polyethylene glycol precipitation method. The neutralizing activity of the purified IgY was evaluated by Vero cell viability assay. This assay confirmed that 1.95 μg (8.6 μg/ml of culture medium) of anti-DT IgY would neutralize 10 fold of cytotoxic dose 99% of DT, which was 0.3 ng (1.33 ng/ml of culture medium).ConclusionThis anti-DT IgY may be applicable for diphtheria treatment and quality controls in vaccine production.

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

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. 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. 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. 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.

Park's story and Winters' tale: alternate allocation clinical trials in turn of the century America.

In 1898, Johannes Fibiger of Copenhagen, in the setting of scepticism about the efficacy of diphtheria antitoxin, famously allocated 484 patients admitted to his hospital on alternate days to either receive or not receive antitoxin in order to test its utility.1–3 Over the subsequent half-century before the Medical Research Council's randomized control study of streptomycin for pulmonary tuberculosis, alternate allocation would emerge as an increasingly utilized and respected methodological tool for determining therapeutic efficacy.4–6 Yet the advent and early dissemination of this methodology – and the resistance to its wider application – is only now beginning to be seriously researched. William H Park (1863–1939), the longstanding director of the laboratories of the New York Board of Health, has been justifiably honoured for having saved countless lives through the use of diphtheria antitoxin and immunization in New York City at the end of the 19th century and beginning of the 20th century.7 During those same years, Park was closely associated with some of the most sophisticated and visible therapeutic trials in America (and the world). In addition to using alternate allocation of patients to treatment comparison groups, they used double-blinding,8 multisite collaboration, and statistically compared treatment groups, including the use of statistical synthesis (meta-analysis).9 Park would claim, like Fibiger, to have first conducted such an alternate allocation study in the 1890s in the setting of scepticism regarding the utility of diphtheria antitoxin. Yet a deeper investigation of the context of Park's apparent study reveals not only a surprise twist, but important insights into the advent of, and resistance to, the alternate allocation method in the United States, and possibly further afield.

Classics in clinical science: The concept of renal clearance

A major share of the advances in medical knowledge has come about through the work of clinical investigators who applied the methods of science to the study of disease. Their skill in identifying important problems at the bedside and constructing practical solutions which enlarged the scientific base of medical practice, has resulted in tremendous advances in the armamentarium of every physician. In the climate of today, when the clinician eagerly utilizes the methods of the laboratory, it is difficult to believe that early in this century clinicians looked with suspicion upon newfangled things and basic scientists had disdain for research carried out by clinicians. This earlier attitude of clinicians is typified by the story told David L. Edsall by President Eliot of Harvard. Mr. Eliot had forced through the faculty of the Harvard Medical School the establishment of a course on bacteriology and the appointment of Dr. H. C. Ernst, who had recently returned from study in Europe, as the teacher of the subject. There had been violent opposition to the establishment of a course in so new a subject of questionable value and a professor of pediatrics had been especially violent in opposition. Methods for demonstration of the diphtheria bacillus were already available for diagnosis, and soon after Ernst’s appointment the use of diphtheria antitoxin was introduced. Dr. Ernst was the only man in the city who knew how to recognize the bacillus or to make an antitoxin. One day Mr. Eliot met the professor of pediatrics coming from Dr. Ernst’s laboratory, and said to him: “Doctor, isn’t this an odd place for you to be?” He replied: “Yes, but nowadays one has to come here for a diagnosis and now we have to come here for our treatment.” This attitude continued in some degree, however, for long afterwards. When Edsall went to Harvard as Jackson Professor of Medicine in 1912 Mr. Lowell, who had been president of Harvard University for three years, told him that at faculty meetings the clinicians sat on one side of the table, the laboratory men on the other, and each opposed the other in everything. A physician-scientist who was equally at home at the bedside and at the laboratory bench was Thomas Addis [l]. Born in Edinburgh in 1881, he came to this country in 1911 to take over the clinical laboratory at Stanford under Ray Lyman Wilbur. Addis’ genius for research soon led him to cast off the burdens of the routine laboratory and within a short time his important studies on the kidney were launched. In collaboration with various associates, his investigations of renal disease brought a continual output of excellent work until his retirement in 1948. He first studied the physiology of the kidney but soon embarked on investigations of disordered structure and function in Bright’s disease. Addis and others at Stanford were stationed at Camp Lewis, Washington, during World War I. While there they made important observations on blood pressure and pulse rate, similar to those made by Horace Smirk on basal blood pressure many years later. It was after his return to Stanford at the end of the war that Addis began his investigations into urinalysis and renal function. One of his classic contributions appeared in the first issue of the Journal of Urology in 1917 [2] entitled “The Ratio Between the Urea Content of the Urine and of the Blood After the Administration of Large Quantities of Urea. An Approximate Index of the Quantity of Actively Functioning Kidney Tissue.” This paper began with a penetrating review of the previous work on the testing of renal function and then was followed with Addis’ own rationale for developing the “urea ratio “: “the ratio between the urea content of the urine and of the blood (UV: B) expresses the number of times by which the urea excreted in the urine during a certain period of time exceeds the amount of urea present in 100 cc of blood supplied to the kidney during

Safeguarding the Public Health: Newark, 1895-1918

Stuart Galishoff examines the effects of germ theory on the work of the Board of Health of Newark, NJ, in the early years of the 20th century. Street cleaning and garbage collection gave way, under the impetus of bacteriology, to the use of specific remedies for contagious diseases. Although slow to respond to pressing health needs of the immigrant population in the second half of the 19th century, Newark's Board of Health surged ahead rapidly in the 20th, adopting new techniques in its search for a healthier city. The bacteriology laboratory established in 1895 led the revival. Quick success with the use of diphtheria antitoxin established the laboratory's reputation and paved the way for improvements in the quality of the city's water and milk, in sewage disposal, and mosquito control. Infant mortality greatly diminished, malaria and tuberculosis rates decreased, and the board turned its attention to new concerns such as

Diphtheria antitoxin (dip/ser) BP

Diptheria Antitoxin has again become available from the Lister Institute. It contains 4000 international units/ml of refined anti-diptheria globulin prepared from horse serum and is intended for the prevention of diphtheria in susceptible persons exposed to risk of infection, and for therapeutic use. A dose of 500 – 2000 units by intramuscular injection is sufficient to protect a diphtheria contact for about two weeks. When used for this purpose it should always be combined with active immunisation, the antitoxin being given in one arm and the first dose of adsorbed toxoid in the other. For therapeutic use antitoxin is given as soon as possible after diagnosis as an intravenous or intramuscular injection of 10,000 – 100,000 I. U. according to the clinical picture. The use of diphtheria antitoxin may result in serum sickness or anaphylactic shock particularly in allergic patients and in those who have previously received an injection of horse serum. Therefore it is advisable to defer treatment until 30 minutes after a test dose, instructions for which are provided by the Lister Institute. When the administration of antitoxin is undesirable, contacts in a closed community can be given penicillin or erythromycin instead of antitoxin.

FATAL SYSTEMIC ANAPHYLAXIS IN MAN.

THE use of diphtheria antitoxin near the turn of the century ushered in a period of serum therapy that accounted for many reports of fatal systemic anaphylaxis in man. Some of these cases were tabulated in 1924 by Lamson1 and in 1930 by Sheppe,2 who noted that autopsy data were obtained in only 15 cases and were not always adequately detailed. With the development of vaccines and normal or immune gamma globulin serum therapy has become less frequent, and penicillin administration is currently the major iatrogenic cause of systemic anaphylaxis.3 , 4 Skin testing,5 insect bites6 and intravenous urography7 less frequently result . . .

Virulence of tubercle bacilli; in vitro testing by the use of diphtheria antitoxin.

Virulence of tubercle bacilli; in vitro testing by the use of diphtheria antitoxin.

A critical consideration of some immunological problems with special reference to diphtheria

I N this Address I hope to provide a reply to a question which was recently put to me by a colleague who said: " Do you still believe in the work you are doing with sera?" My questioner was clearly very sceptical of the value of serology as applied in practice, and the scepticism is one which is shared by many members of the profession. Opposed to it is the blind faith with which the value of immunological products, whether in the sphere of passive or active immunity, is accepted by so many others. Their most active protagonists will ask you to accept without question what they choose to tell you concerning them, and it will be my endeavour to analyse impartially some of the evidence on which their boldest assertions rest. I shall confine myself largely to consideration of what we know about diphtheria not alone because of the importance of this disease but because the value of immunological products for the treatment and prophylaxis of human disease is most usually assessed by the results which have been obtained with diphtheria antitoxin and diphtheria prophylactics. Let us first consider the evidence on which claims are based for the use of diphtheria antitoxin in the treatment of diphtheria. There are only two experiments on the clinical use of diphtheria antitoxin which would be capable of providing first class evidence of its therapeutic value. Of these the experiment performed at the Blegdams Hospital in Copenhagen by Fibiger (1898) is regarded by some as the most complete of its kind. His method was to treat all cases without selection a.dmitted on one day with antitoxin and the next day without antitoxin, alternating in this manner for a period of one year. In all, 484 cases were recorded, 239 with antitoxin and 245 without. Of the 245 untreated, 30 died, giving a case mortality or fatali ty rate of 12.2 per cent. Against this, 8 deaths among the 239 in the treated group gave a fatality rate of 3.3 per cent., a notable reduction. But in the light of modern experience Fibiger's results are much less convincing. He was dealing with a type of diphtheria in which the fatality-rate was only 12.2 per cent. in the untreated cases, a diphtheria of such mild character that its fatality-rate without specific treatment is already as low as the rate found to-day in many areas in which specific treatment is employed in conjunction with the chemica! and mechanical aids to therapy which have been developed since his time. This is illustrated in

DIPHTHERIA INFECTION OF ANTRUM

To the Editor: —InThe Journal, October 2, under Queries and Minor Notes, a physician in Connecticut inquires regarding a diphtheria infection in the antrum of Highmore. In 1924, I had a similar case. The patient was superintendent of public schools in a nearby town. Cultures sent to the state laboratory were pronounced nonvirulent, which probably accounted for the fact that there were no contact cases. The infection was resistant to washings but cleared up promptly after the making of adequate drainage under the turbinate and the use of diphtheria antitoxin directly into the antrum.

DIPHTHERIA

With the aim of bringing the diphtheria situation in American cities to general attention, and in the hope that methods found available for reducing diphtheria in one locality may be made familiar and be utilized in others,The Journal of the American Medical Associationhas undertaken an annual general survey of diphtheria mortality in American cities of more than 100,000 inhabitants, similar to the typhoid surveys published for several years past.1 The tables include sixty-eight cities of over 100,000 population and are arranged in geographical groups. They show clearly the decline in diphtheria mortality with the introduction of the use of diphtheria antitoxin in 1894 to 1895. However, the rates since that time have not continued to fall in some sections as it seems they should. The composite table shows the effect of the use of antitoxin. In the period since 1910, the decline in the diphtheria rate for

DERMATITIS DIPHTHERITICA

That the Klebs-Loeffler bacillus may produce cutaneous eruptions is well known. Dermatitis diphtheritica may be primary, or, which is usual, may result from contamination from mucous membrane lesions. These secondary eruptions were, until the introduction and wide spread use of diphtheria antitoxin, not uncommon. On the other hand, primary cutaneous diphtheria is either very rare or, because not very often diagnosed, commoner than is generally thought. This undoubt

SUDDEN DEATH ASSOCIATED WITH THE INJECTION OF FOREIGN SUBSTANCES

The year 1894 marks the beginning of the use of diphtheria antitoxin in the treatment of diphtheria, though it was not used extensively until several years later. Since 1894, other antiserums have been produced, and other methods of nonspecific and specific protein therapy have been devised. During the last ten years, in consequence, the use of such antiserums and foreign proteins has increased enormously. In the course of this development of serum therapy, some serious and even fatal accidents have been observed. A number of fatal cases have been reported in the literature, and it may rationally be assumed that a certain number have occurred but have never been so reported. The actual number of cases in both groups is generally much overestimated. Only a few attempts have been made to compile and study the records of the reported cases. One of these, by Gottstein,¹gives a brief summary

Book Review Prophylactic Use of Diphtheria Antitoxin . Dr. James A. Doull, Associate Professor of Epidemiology, School of Hygiene and Public Health, the Johns Hopkins University, and Dr. Roy P. Sandidge, Passed Assistant Surgeon, United States Public Health Service, have recently published the results of an investigation into the prophylactic use of diphtheria antitoxin, under the caption "Is the Prophylactic

Book Review Prophylactic Use of Diphtheria Antitoxin . Dr. James A. Doull, Associate Professor of Epidemiology, School of Hygiene and Public Health, the Johns Hopkins University, and Dr. Roy P. Sandidge, Passed Assistant Surgeon, United States Public Health Service, have recently published the results of an investigation into the prophylactic use of diphtheria antitoxin, under the caption "Is the Prophylactic

Importance of Early Use of Diphtheria Antitoxin

Importance of Early Use of Diphtheria Antitoxin

The anaphylactic response of the human fallopian tube

The material for this study was obtained in the routine course of gynecological operations, through the courtesy of the surgeons. In the operations for fibroid tumors of the uterus, it is frequently necessary to remove the Fallopian tubes, which furnish a satisfactory basis for the study of smooth muscle reactions. The tubes were studied by the method described by Dale for the uterine horns of the guinea-pig. Some of the material came from women who had previously received horse serum in some form, while in the remainder, regarded as controls, there was no history of the use of diphtheria antitoxin, or other therapeutic serum derived from the horse. The tubes which came from the sensitized individuals presented a distinct response upon the addition of minute amounts of horse serum, while the controls failed to respond even on the addition of large amounts of horse serum. The contractile response, although much less pronounced than in the case of the guinea-pig, is still unmistakable. The response to ergamine, adrenalin, and other similar drugs, is also very much less marked, in the case of the human preparation. From an anaphylactic standpoint, the human smooth muscle is, therefore, intermediate between that of the guinea-pig and that of the rabbit. This fact explains the character of the anaphylactic symptoms which have been observed in human beings.

INTRAVENOUS INJECTION OF DIPHTHERIA ANTITOXIN IN CHILDREN

The benefits of the antitoxin treatment of diphtheria are well recognized. From 1878 to 1894 in New York City the deaths from diphtheria per hundred thousand of population ranged from 110 to 264 and from 1890 to 1895 the combined diphtheria deaths in the larger European and American cities from 66.9 to 80.4 per hundred thousand population, while following the general use of diphtheria antitoxin since 1895 the deaths per hundred thousand of population have varied in New York City between 22 and 91, and between 19 and 55.6 in the larger cities of the world. Diphtheria antitoxin was first used generally in 1895 and in 1896 first manifested its real value in the United States. Gradually fewer deaths from diphtheria have occurred, but it must be evident that in the past few years the death-rate has not been decreased materially. That we still have some deaths due to the

ACTIVE IMMUNIZATION AGAINST DIPHTHERIA BY MEANS OF VON BEHRING'S VACCINE, AND THE DIPHTHERIA TOXIN SKIN REACTION

The weak point in the immunizing use of diphtheria antitoxin lies in the short duration of the passive immunity thus conferred. The injected antitoxin is rapidly broken down and eliminated until in the average case there is not sufficient antitoxin left at the end of ten days to afford further protection. (Von Behring, Park.) While this ten day period may be enough to protect the average individual who has been in contact with a case of diphtheria, it is not adapted to protect those who are constantly or repeatedly exposed to infection, as for example nurses or physicians on service in a diphtheria ward, or patients in the wards of a children's hospital. The rapid destruction and elimination of antitoxin is due in large part to the use of a serum obtained from an animal of a foreign species. Park found that if a guinea-pig received 10 units of diphtheria

TWO CASES OF ANAPHYLACTIC SERUM DISEASE OVER SIX YEARS AFTER THE PRIMARY INJECTION OF HORSE-SERUM (YERSIN'S ANTIPEST SERUM)

The widespread interest in hypersusceptibility and allergy and their relation to infectious disease leads me to report two cases of this nature following over six years after the primary injection of horse-serum. I desire also to express the personal feeling that the use of diphtheria antitoxin for the immunization of contacts (the immunizing dose) should be avoided as often as practicable. I believe it is much wiser and shows more consideration for the patient for contacts to be examined from day to day and for cultures from the throat to be examined as well. In this way the disagreeable features of serum disease and the indiscriminate and widespread sensitization of many persons to horse-serum will be avoided. Serum disease is a term used by von Pirquet and Schick¹to denote the clinical manifestations following the injection of horse-serum. These symptoms may follow the primary, secondary, or other subsequent injec