Diphtheria is now a rare infection in Great Britain. The major credit for this state of affairs must be given to prophylactic inoculation of children with toxoids. It would seem possible, however, that with the passage of time public awareness of the disease diminishes so that immunization is not undertaken until entry to school in a considerable proportion of the child population. Local epidemics—often associated with mortality—have now occurred in a number of places so that there is real need to bear in mind the possibility of its reappearance.
Diphtheria is almost entirely a toxic disease. Although some slight tissue invasion takes place in severe infections, for the most part the organisms remain localized to the site of inoculation from which the toxin diffuses by lymphatics and blood stream to all parts of the body. The ability of the host to neutralize toxin thus constitutes an almost complete defence ; for, shorn of its toxic action, the diphtheria bacillus is a weak pathogen.
C. diphtheria is divisible by cultural methods into three main types—grains, intermedius and mitis. Broadly speaking, the first two are associated with a more severe form of the disease. Bacteriological typing is not of immediate importance to the clinician, who must estimate the initial dose of antitoxin before such information is available. The subsequent progress of the case, however, should be governed to some extent by the results of typing; gravis and intermedius infections should be supervised more strictly since complications are more frequent. Further, almost all gravis and intermedius strains are virulent, so that a carrier of these types may be regarded as harbouring pathogenic organisms. Mitis strains are frequently non-virulent, and a virulence test is essential before the final assessment of a carrier can be made. The importance of typing in epidemiological work will be obvious.
Cases and carriers constitute the main sources of infection. Usually the bacteria are carried in the throat or nose, the latter site being rather more common, so that in a search for a source of infection nasal cultures should never be omitted. Cutaneous diphtheria, often simulating a chronic sore, may be an unsuspected source of infection. Although in most instances infection is spread by droplet infection, contaminated milk, ice-cream and food have initiated local outbreaks.
The importance of the early diagnosis of diphtheria cannot be too strongly emphasized. Careful examination of the fauces should be a routine procedure in every febrile patient. Apart from the presence of " false membrane ", marked faucial and palatal oedema, accompanied by an acute gross enlargement of the cervical glands, should, in a child, always be treated as diphtheria until proved otherwise.
Diphtheria is a notifiable disease. It has an incubation period of two to five days.Prevention and Epidemiological Control.—Schick Test.—Susceptibility to diphtheria can be ascertained by the application of the Schick test—an intradermal injection into the left forearm of 0-2 ml. of diluted diphtheria toxin. Individuals showing an area of erythema from i to 4 cm. in diameter around the site of injection four to seven days after the application of the test are said to be Schick positive, an indication of susceptibility to the disease. When applying the primary Schick test to a large community, the highest proportion of positive results will be obtained when the reactions are read on the seventh day. No local reaction appears in those who are immune (Schick negative reactors). A precisely similar injection is made into the skin of the right forearm, but with toxin which has been previously inactivated by heat.
This control test discriminates between local reactions arising from sensitization to the protein present in the test fluid and the true positive Schick reaction. Reliable Schick and control test material can be obtained commercially.
Active Immunization.—Every child should be actively immunized against diphtheria during the first year of life. A preliminary Schick test is unnecessary.
Four vaccines1 are available : purified toxoid aluminium phosphate (PTAP), alum-precipitated toxoid (APT), formol toxoid (FT) and toxoid antitoxin floccules (TAF). For children under 5 years two intramuscular injections each of 0-5 ml. of one of the alum-toxoids with an interval of four weeks between injections will produce effective immunity. In older children or adults it is better to start with a small dose (0-2 ml.) and observe the degree of local reaction. If this is severe two further injections of 0-2 ml. with a four-week interval are advised. FT is not recommended since it is a weaker antigen and reactions are common in older children and adults. TAF is a good antigen and remarkably free from local reaction. It has the disadvantage that it contains horse-serum and may, therefore, have a sensitizing effect. Three injections of i-o ml. are required.
The first injection has no permanent immunizing effect. It is the subsequent doses which evoke a high level of antitoxin in the blood and confer immunity. The duration of this immunity is variable, but a child who has received the two immunizing doses may later have its immunity " boosted " by a further single injection. Such a " booster " injection is essential before the child enters school at the age of 5 years.
Combined vaccines are now commonly used. For example, diphtheria-tetanus adsorbed vaccine is a good antigen and remarkably free from local reactions in children. Diphtheria, tetanus and pertussis vaccines are best prepared without alum and in this form are good antigens, but should not be given before the age of three months in order to obtain a satisfactory response to the diphtheria and tetanus antigens. As it is so convenient to obtain this comprehensive immunizing effect with single injections, the method is recommended as a means of obtaining immunity during the first year of life. A quadruple vaccine, containing diphtheria, tetanus pertussis and killed poliovirus antigens, is now available but is not yet recommended for general use since it has been associated with somewhat severe side-effects.
General Measures.—For the control of an outbreak the first steps are the isolation of the patient. Contacts must be carefully examined for evidence of a missed infection. Particular attention should be paid to any person suffering from chronic nasal or aural discharge, or obviously unhealthy tonsils—or a suspicious cutaneous lesion—and the appropriate swabs taken for bacteriological examination.
The normal carrier rate in the general population is exceedingly low so that when a case of clinical diphtheria occurs it is important to try to identify the carrier from whom the infection was conveyed. After a preliminary warning to the bacteriologist when large numbers are involved, swabs should be taken from the nose and, throat and from any suspicious lesion of all contacts. Since the typing of C. diphtheria isolated from either the primary case or the contacts will take three to four days this time may be usefully occupied in eliciting precise1 The term " vaccine " was formerly confined to the description of materials which contained bacteria or viruses. It is now used to describe all antigenic substances designed to secure active immunity.
details regarding the immunization status of those involved. Contacts who have already received a full course in childhood can now be effectively " boosted " by a single injection of 0-2 ml. of an appropriate vaccine (PTAP). Persons who have never been immunized should be given active-passive immunization. To accomplish this 500 units of diphtheria antitoxin is injected into one arm at the same time as 0-5 ml. of PTAP is injected into the other arm. A note should be taken to ensure that these persons are given a further injection of 0-5 ml. of PTAP four weeks later to complete the active immunization course.
Any carriers disclosed by the bacteriological examination must be isolated in hospital and treated appropriately (p. 13). It is nowadays essential to ensure that the carrier state has been effectively eradicated before the individual is released from isolation.
Curative Treatment.—A history of immunization must never lead the practitioner to ignore the possibility of diphtheria. Indeed, it must be appreciated that mild diphtheria—usually due to gravis organisms—occasionally occurs in the inoculated and that such infections are usually atypical and may be more suggestive of tonsillitis. Further, although it is undoubtedly true that the disease in the immunized is often mild, failure to make an early diagnosis may result in the administration of serum too late to prevent nervous complications.
Antitoxic Serum.—An intramuscular injection of at least 4,000 units of diphtheria antitoxic serum should immediately be administered to any patient suspected to be suffering from the disease. The importance of early administration of antitoxin cannot be exaggerated. The doctor who " wonders whether this might be diphtheria " is under an obligation to give serum at once. Swabs can then be taken. By the time full bacteriological investigations have been made, several days must elapse. These are the critical days : omission of antitoxin treatment at this stage may be fatal. There is considerable difference of opinion regarding the optimum dose of antitoxin in the treatment of diphtheria. Broadly speaking, mild attacks require from 4,000 to 8,000 units intramuscularly ; cases of moderate severity from 16,000 to 32,000 units intramuscularly ; severe or toxic attacks from 48,000 to 96,000 units divided between the intramuscular and intravenous routes. When the diphtheritic infection is limited to the larynx, 8,000 units of antitoxin are usually sufficient, and a similar dose is adequate in purely nasal diphtheria unless toxasmia is severe.
There is no satisfactory method of assessing the correct amount of antitoxin, so that it is better to err on the side of overdosage. There are good grounds for believing that a dose of 48,000 units is more than adequate for the most severe case of diphtheria and that it is never necessary to give more than 96,000 units.
The route of administration is very important. It is seldom appreciated that a considerable time elapses after intramuscular injection before " peak " levels are attained in the blood stream. All severe cases (i.e. where more than 32,000 units are to be given) must receive at least part of the dose intravenously. In other words, the intramuscular route is the second-best and should only be used in mild or moderate cases. Intramuscular serum should be given into the lateral aspect of the thigh. (Before giving serum the doctor must be conversant with the possible dangers which may result, and the measures to be taken for their prevention and treatment are discussed Other Specific Treatment.—The bacteriological examination of the throat swab will include search for other pathogens—particularly Str. pyogenes—by suitable culture. Erythromycin has a definite value in the treatment of diphtheria after serum has been given. In the first place it is of value in dealing with the superadded infection so often present; and secondly it hastens the disappearance of C. diphtheria from the throat and reduces the risk of development of the carrier state. The dose must be large (in the range of 10 to la-mg. per kg. body weight) in order to ensure an adequate local concentration.
General Measures.—With the exception of the mildest attack, a case of diphtheria should not be treated at home unless adequate nursing attention is available day and night. From the moment that diphtheria is suspected, the patient must be confined to bed in a strictly recumbent position. Owing to the risk of cardiovascular complications, any attempt to sit up, reach over to a chair or bedside table, etc., must be prohibited. Indeed, in the most toxic forms the patient should not even feed himself. The period of recumbency varies from 14 davs in mild attacks to eight weeks or longer in severe cases, according to the condition of the cardiovascular system and the occurrence of paralysis. The need for strict recumbency is not dictated because of cardiac damage, but because the peripheral circulation is also severely affected.
After the addition of a second and a third pillow at intervals of two clear days, the patient is permitted to sit up, and may leave his bed seven to ten days later. The rate of progress will vary according to the severity of the attack and the response of the cardiovascular system to increased exertion. This is assessed by a study of the pulse rate: a rising pulse rate means that convalescence is being unduly hurried. Care should be taken to curtail activity when the patient begins to walk. Ocular paresis is a possible development and reading should be restricted; the print must be large and the page well illuminated.Complications.—The mitigation of serious toxic damage to the heart and vessels by the earlv application of the measures detailed above is the fundamental principle in the treatment of diphtheria. Once well-marked signs of cardiovascular weakness appear, the situation is grave and treatment other than skilful nursing is of little avail. The foot of the bed should be raised. Vomiting due to cardiac failure necessitates the replacement of oral feeding by the administration of intravenous infusions. The mouth may be moistened with sips of water or pieces of cracked ice. Epigastric pain, restlessness and anxiety are best relieved by repeated hypodermic injections of morphine : 2 mg. for a child of two years, 4 mg. at five years, and 5 mg. for a child of 10 years. The various vasomotor or cardiac stimulants have no place in the treatment of circulatory failure in diphtheria. Drugs of the digitalis group are definitely contraindicated. The administration of alcohol has nothing to commend it. Apart from involvement of the pharyngeal and respiratory muscles, noanxiety need be felt regarding the outcome of the post-diphtheritic palsies, since they tend to recover spontaneously within a few weeks. In palatal paresis the fluid part of the diet should be replaced by semi-solids. In pharyngeal paralysis the foot of the bed should be raised 18 in. and the patient nursed in the prone position. Saliva and mucus should be aspirated at frequent intervals from the pharynx and food administered by nasal tube. On the slightest indication of weakness of the intercostal muscles or diaphragm constant supervision is essential. The degree of respiratory dysfunction must be carefully assessed and the necessary preparations made for instituting mechanical assistance. Late generalized muscular weakness improves with massage, hot and cold douching, graduated exercise, fresh air and good food.
Convalescence.—It is necessary to obtain three consecutive negative cultures from both throat and nose at an interval of one week before the patient is released from isolation. Even after a mild attack the patient should not resume school or work for at least a fortnight after isolation is stopped. The convalescent period may require to be prolonged to six months or even longer following severe toxic diphtheria. Strenuous exercise must be forbidden.
CARRIERS
The first essential in dealing with a persistent convalescent—or contact— carrier of morphological diphtheria bacilli is to make sure that the organisms are virulent. Carriers of non-virulent bacilli are not dangerous to the community and need not be segregated.
If the organism isolated is virulent, tests to disclose its antibiotic sensitivity should be requested. Erythromycin is usually particularly effective against C. diphtheria and, while awaiting the laboratory results, its administration may be started. The estolate is a suitable preparation and a daily dosage in the range of 10 to 15 mg. per kg. body weight should be used. This will ensure a high local concentration. Erythromycin should be continued for 10 days and during this time the carrier must be strictly isolated in order to prevent re-infection.
While treatment is proceeding the time can be used to make a detailed clinical and radiological examination of the mouth and upper respiratory tract since, in persistent carriers, it is common to find some local abnormality which serves to prolong the carrier state. At the end of the course of treatment it is advised that six negative cultures from the nose and throat should be obtained over a period of at least 14 days. This period should not be shortened for it is often found that negative swabs may give place to positives at the end of the series. Should erythromycin fail the question of further chemotherapy may be considered in light of the known sensitivity of the organism. However, when the examination of the nose and throat has disclosed some abnormality which j should be corrected surgically it will usually be preferable to adopt this course for, in such circumstances, cure may prove exceedingly difficult with chemo-; therapy alone. The effective clearing of carriers is now all the more important because of the very low carrier rate in the community.
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