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The Acute Infectious Diseases
THE ACUTE INFECTIOUS DISEASES ARCHIBALD
L.
HOYNE,
M.D. o
GREAT changes have occurred within recent years in respect to nearly all the acute infectious diseases. Diminished prevalence, fewer serious complications and lower fatality rates have been observed in allnost every section of this country. Something more than progress in methods of immunization and introduction of new forms of therapy has contributed to these improvements in the general state of the public health. Advancement in sanitary science has been a powerful force in the curbing of mortality. Moreover, better homes and a higher scale of living have undoubtedly led to an improved state of nutrition. As a consequence, it seems reasonable to assume that resistance to infection has increased even if pathogenic organisms have not lessened their virulence. But if there has been both an increase of resistance to infection in the general population and also a diminishment in the virulence of disease, then death rates should have declined, even without improved methods of treatment. This last situation seems· to exist in respect to certain diseases, notably smallpox and scarlet fever.
DIPHTHERIA
Diphtheria may be linked with smallpox from the standpoint of prevention, which is the only certain means of eliminating mortality from these diseases. The most expert care will not save the lives of all diphtheria patients. Even in the largest cities, however, remarkable success in stamping out diphtheria is possible when a program of immunization is well planned and energetically directed. Chicago is a good illustration of such an accomplishment. Figures from the Municipal Contagious Disease Hospital serve as an index of declining diphtheria prevalence in that city. In the year 1921, there were 2165 diphtheria patients admitted, in contrast to only twenty-three admissions, with one fatality in 1945. . Chicago's record in respect to diphtheria is particularly cheering at this time when the disease is said to have an increased incidence throughout most of the war-torn world. Even in this country, the United States Public Health Service reports that diphtheria has risen 24' per cent during the first three months of 1946, as compared with the nrst quarter of 1945. From Cook County Hospital, Chicago. o Attending Physician and Chief, Contagious Disease Deparbnent, Cook CoUnty Hospital; Clinical Professor of Pediatrics, University of Chicago School of Medicine. 61
62
ARCHIBALD L. HOYNE
Treatment.-For the treatment of diplltlleria patients, the mere administration of diphtheria antitoxin is not always sufficient. Absolute rest is sometimes equally important because of the danger of myocardial weakness. In serious cases the patient should not even raise his head from the bed. When myocarditis develops it is not likely to be detected prior to the tenth day of disease, and the slightest exertion may then be disastrous. If the patient has been ill without antitoxin for three or more days, we give 10 per cent glucose in distilled water intravenously each twenty-four hours for at least eight days. The amounts usually vary from 500 cc. to 1000 cc., depending on the size of the patient. We believe that if 60,000 units of diphtheria antitoxin will not bring about recovery in a patient, he will seldom get well on double that amount. It is best to inject the antitoxin in the outer muscles of the thigh. Since the adrenals are often dama~ed in severe types of diphtheria, adrenal cortical extract in doses of from 3 cc. to 5 cc. once or twice daily seems to be helpful in some instances. It is also our impression that for severe cases penicillin is a valuable adjunct in treatment. This drug is given in doses of 10,000 to 20,000 units intramuscularly every three hours. As long as a diphtheria patient has a pronounced albuminuria, he should not be regarded as out of danger. The presence or absence of albuminuria is exceedingly dependable as a prognostic guide. Carriers.-PeniciIIin appears to be of value in freeing the nose and throat of diphtheria organisms. For this purpose the drug may be used as a spray, given' in tIle form of a lozenge or injected in tIle muscle. The removal of tonsils and adenoids is likely to be successful when other measures fail. SCARLET FEVER
Scarlet fever provides some of the most difficnlt problems in the field of public health. Whether or not it is controllable depends somewhat upon our conception of the disease. If scarlet fever can occur without a rash, it is not likely to be recognized, and so the individual may convey the infection to others. A patient with a diagnosis of streptococcic sore thrQat is likely to be admitted without question to any general hospital. However, if a rash is observed, the disease is called scarlet fever and the patient is excluded. Nevertheless, the inciting organism may be the same in both instances. A large percentage of an urban population often harbors llemo]ytic streptococci in the nose or throat. This situation in respect to hemolvtic streptococcus carriers among the civilian population llas been reflected in military centers and has sometimes resulted in many cases of scarlet fever. An increase in scarlet fever generally' means an increase in rheumatic fever and, therefore, the former disease becomes of major importance. There is no known method of establishing active immunity against
11IE ACUTE INFECI'IOUS DISEASES
63
streptococcic infections. Consequently, if we acknowledge that scarlet fever can occur without a rash we lnust also admit that there is no agent available for inducing active immunity against this form of scarlet fever. Scarlet fever is far less prevalent and much milder today than only a few years ago and, consequently, deaths are fewer. Treatment.-Serious and even fatal cOlnplications have sometimes followed what appeared to be a mild attack of scarlet fever. Therefore, even though the patient may not seem to be very ill, it is often advisable to administer one of the following therapeutic agents: convalescent scarlet fever serum, scarlet fever antitoxin or penicillin. The sulfonamides are not included here in the list of remedies, because we ,believe they do not influence the toxemia of scarlet fever. Nor do the sulfonamides seem to serve as a prophylactic against complica.. tions, although they are of value in treating certain complications. Convalescent scarlet fever serUln in doses of 20 cc. or more is of value. Because of a number of kno\vn instances in which acute hepatitis followed the injection of pooled human serum,· however, there are now some \vhooppose the use of human convalescent scarlet fever serum. Convalescent scarlet fever serum may be given intramuscularly or intravenously at any stage of the disease but preferably early. Scarlet fever antitoxin in doses of 9000 units consists of only about 5 cc. or less by volume. It is now so highly concentrated and re.. fined that unpleasant reactions are rare. To be effective, it should be given before the rash has disappeared, whicll means, as a rule, before the third day of eruption. It should be injected in the muscle. It is not recommended for the ·treatment of complications. Our experience during the last year and a half with the use of penicillin suggests that this new drug is a useful remedy for scarlet fever. TIle intramuscular injection required for its greatest effective'ness is, however, a disadvantage in adlninistration. Treatment consists in the injection of the drug in 10,000 to 15,000 unit doses every tllree
hours.
It is stated that penicillin, when given in adequate dosage, will elitninate hemolytic stre!Jtococci from nose and throat within seven days. When used orally or in the form of a spray, penicillin is not so effective for eradication of hemolytic streptococci. Lately, penicillin in peanut oil has been made available. It is claimed that when tllis preparation is injected, in 300,000 unit doses intramuscularly about every three days it is as effective as. when smaller doses are injected every three hours. We have not yet had sufficient experience ,vitll the oil preparations to judge their usefulness. There are some who strenuously object to the use of pencillin in peanut oil on the grounds that sensitization is not infrequent and that asthmatic attacks are produced.
64
ARCHlBALD L. HOYNE
.
IlEASLES
Mter the first six months of life susceptibility to measles is practically universal at any age for those who have not had the disease. Before six months measles is uncommon, and under four months the disease is rare. It may be assumed that one attack of measles confers a lifetime immunity. There is no known method for establishing an artificial active immunity. Passive immunity may be accomplished in one of several ways: Convalescent measles serum in doses of 7.5 to 10 cc.; immune globulin (placental extract) 2 cc. to 5 cc., or the newer preparation developed through the processing of blood by the Red Cross, garrl,rna globulin, 2.5 cc. to 5 cc. To be effective for prevention, anyone of these substances should be given by the intramuscular route within three days of exposure. If it is desired to modify an attack of measles, five to six days should be allowed to elapse after exposure before making the injection. For prevention, sometimes two doses of the material are given: the first dose as soon after exposure as possible and a second dose five to six days later. It must be remembered this is merely a temporary protection that may endure for only two or three weeks. If the patient has a modified or attenuated attack of measles, immunity is likely to be permanent, although this is sometimes questioned. Treatment.-Measles is a respiratory disease, and this fact should be kept in mind. Good ventilation is a requirement for proper care and undoubtedly lessens the possibility of a complicating bronchopneumonia. The value of amidopyrine, to which we were probably the first to call attention many years ago, ·has not been altered in my opinion. This drug may be given in doses of 1 grain (0.065 gm.) per year of age up to 5 grains (0.33 gm.), which was our original maximum. It is administered from three to four times daily for a period of three to four days and is best prescribed in a vehicle because in tablet form it occasionally causes nausea. I have never seen any harm result from the use of this drug when given in the manner described. Amidopyrine reduces fever, lessens cough, and apparently diminishes complications. It is mucll more effective than acetylsalicylic acid. Convalescent measles serum even in large doses is of doubtful value, and the use of gamma globulin for treatment does not seem to be justified. For patients with bronchopneumonia nothing is superior to the oxygen tent. Sulfadiazine, sulfathiazole and penicillin are beneficial. Measles Encephalitis.-It has been estimated that encephalitis develops in about one in one thousand cases of measles. This complication seems to be much more frequent than twenty years ago. Measles encephalitis when present generally occurs before the rash has disappeared, usually on the fourth or fifth day of the eruption. The patient's future is always in doubt. More than one third of our
THE ACUTE INFECTIOUS DISEASES
65
patients have seemed to make a complete recovery; sometimes, as many as one third have died, and others were left with permanent mental defects. The spinal fluid findings are not of diagnostic or prognostic significance. The fluid has a normal appearance and the cell count may be normal or increased, sometimes to 200 or more cells, which are nearly all lymphocytes. Treatment.-Treatment of measles encephalitis often includes the use of an oxygen tent. The administration of 10 per cent glucose intravenously by the drip method is of value. We have frequently given also 200 cc. or more of measles convalescent serum intravenously. Whether this latter procedure actually has any specific value is doubtful. Plasma as a substitute for convalescent serum when given in equal volume is probably as helpful. Whole blood transfusions are undoubtedly beneficial in some cases. Feeding by gavage may be necessary. Bronchopneumonia may terminate the patient's existence and, therefore, one of the sulfonamides or penicillin or both are often prescribed with the hope of forestalling tllis final complication. After the temperature has returned to normal we have given some of our patients benzedrine sulfate in 5 mg. doses once or twice a day. A few patients seemed much more alert after this treatment. WHOOPING COUGH
In recent years pertussis has accounted for more deaths than nearly all the other common contagious diseases combined. It is particularly fatal during tIle first year of life. There is now available a number of vaccines for the prevention of whooping cough. Sauer's vaccine is undoubtedly the most popular in the Midwest. It is administered subcutaneously in three doses of 1, 2, and 3 cc. each at monthly intervals. Since each cubic centimeter contains 15 billion killed organisms (Hemophilus pertussis), the entire immunizing dose is 90 billion organisms. Generally, it is recommended that antipertussis inoculations should not be given before the second half year of life. Eight months is often the age selected for this purpose. The reason for not making these injections early is because of the lack of antigenic response during the first few months of the baby's existence. However, it requires about four Inonths to build up immunity, and if immunization is not undertaken prior to eight months, protection cannot be secured before one year of age. Consequently, those in early infancy who are in greatest need of a safeguard from pertussis are denied this benefit. In 1940, the Committee of the American Academy of Pediatrics for the State of Illinois recommended in a pamphlet distributed by the lllinois State Department of Health that whooping cough immunization be undertaken at three to four months of age. This advice was
66
ARCHIBALD· L. HOYNE
given on the theory .that. everi '"if 'complete protection was not secured, a modified attack might occur:u whooping cough was acquired, thus reducing the fatality rate, which is highest for those under one year
of By age.me'ans 'f ,. f·· t·· ft· · h 0 a serIes 0 . InJec Ions 0 per USSIS vaCCIne, t e pregnant woman is sometimes treated for the purpose of transmitting immunity to the unborn child. Success has been claimed by resorting to this method. Pertussis vaccine may be administered alone or in combination with either diphtheria alum-precipitated toxoid or tetanus alum-precipitated toxoid or both. Human hyperimrnune pertussis serum may be us.ed for passive immunity. There is no\v' available a 11ighly concentrated human hyperimmune serum which is sold under the name of Hypertussis. This product appears to 'be of undoubted value. It is injected intramuscularly in doses of from 2.5 to 5 cc. Treatment.-Good ventilation, expert nursing, and proper feeding are the prime requisites for the average case of whooping cough. Regardless of age, it is better to give nourishment in small amounts on many occasions than to give large quantities of food at greater intervals. If a baby suffers a paroxysm after takin~ its bottle, the contents of the stomach are likely to be evacuated. Under such circum.. stances about fifteen minutes are allowed to elapse and another bottle contaIning the prescribed formula is provided. It is very necessary that proper nutrition shall be sustained. Patients with cyanosis or convulsions should be placed in an oxygen tent and may benefit from blood transfusions or hyperimmune serum.' Hyperimmune rabbit serum has been available for some time but the concentrated human hyperimmune serum is a newer product. For infants under one year' of age, concentrated human hyperimmune pertussis serum maybe given intramuscularly in doses of 2.5 cc. and repeated if necessary. Patients of any age should have the services of an oxygen tent when bronchopneumonia is present. Carbon dioxide has also been used, but we now believe this is unnecessary. Sulfathiazole or sulfadiazine is of value, and on some occasions penicil.. lin has seemed to be definitely worth 'Yhile when there are mixed infections. Although it has been reported that streptomycin is effective for the treatment of pertussis, the dru~ has not been sufficiently plentiful to permit many to pass on its merits. In hospital practice in Chicago we rarely resort to sedatives and prefer not to do so. However, if sedation is deemed necessary, chloral hydrate 5 to 10 grains (0.33 to 0.65 gm.) may be given by rectum or sometimes 3~ to ~ grains (0.032 to 0.05 gm.) of seconal in a similar manner. For patients in the home, luminal in doses of 1" to 3 grains (0.1 to 0.2 gm.) may prove to be very satisfactory.
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67
MENINGOCOCCIC MENINGITIS
Undoubtedly the greatest progress in the treatment of acute infectious diseases in recent years pertains to the meningitides. In the past, practically all forms of bacterial meningitis were usually 100 per cent fatal with the exception of the meningococcic variety. In the case of the latter, although there had been a specific antiserum in common use since 1907, the results were far from satisfactory. Gover and Jackson state that the case fatality rate of cerebrospinal meningitis was 55 per cent in 1980 for the country as a whole, and that it was 39 per cent in 1940. Prior to 1940, the year sulfonamides came into general use, the accepted method of administering serum was by the intrathecal route. In addition, frequent drainage of cerebrospinal fluid to relieve intracranial pressure was regarded as imperative. For these two purposes, daily lumbar punctures were considered a necessity. In some eastern hospitals this procedure was carried out as often as every six hours during the first few days. Even when Schwentker first reported the use of sulfanilamide for meningococcic meningitis, he injected the drug intrathecally. Soon after beginning our clinical trial of Ferry's newly developed meningococcus antitoxin at the Cook County Hospital in 1934, we discontinued all intrathecal treatment in favor of the intravenous route. We also abandoned the long existing theory that repeated withdrawals of spinal fluid were necessary to relieve intracranial pressure. Furthermore, it was found that patients made excellent recoveries without any spinal puncture. The clinical diagnosis was confirmed by either a positive blood culture for meningococci or by a positive smear from petechiae when the latter were present. During the few years of exclusive intravenous therapy at the Cook County Contagious Disease Hospital and also at Municipal Contagious Disease Hospital, we sometimes had lower fatality rates for meningococcic meningitis than we have ever had since the introduction of the sulfonamides. Much of our success was attributed not merely to the fact that large doses of serum were administered intravenously but because no irritating substance was injected intrathecally. Therefore, it is my opinion that a share of the remarkable efficiency of sulfonamide therapy should be attributed to the omission of intrathecal serum. Unfortunately, with the coming of penicillin, after intrathecal therapy had at last been reluctantly discarded by many, there has been a disposition to resort again to intraspinal treatment. Yet, even those who advocate the administration of penicillin intrathecally admit the disadvantage of the method and confess that adhesions, blocks and other complications sometimes occur. We continue to believe that intrathecal therapy is not only unnecessary for any kind of meningitis but that it may be actually harmful.
68
ARCHIBALD L. HOYNE
Treatment.-The management of meningococcic infections may be as follows: If petechiae are present, scarify one of the lesions, make a smear, stain and examine for gram-negative diplococci. Regardless of whether organisms are found in smear or not, always obtain blood for culture. The patient may have meningococcemia without clinical evidence of meningitis. If smear or blood culture is positive, a spinal puncture is not necessary. If the patient has no petechiae, a lumbar puncture is essential for examination of spinal fluid and prompt laboratory diagnosis. Any of the principal sulfonamides may bring about recovery. Sulfadiazine, sulfathiazole and sulfamerazine are the chief ones for consideration. For practical purposes it is not obligatory to determine dosage on the basis of patients' weight but rather on the severity of the disease. For children under five years our initial dose of the drug selected is usually from 2 to 3 gm., followed every four hours by from 0.5 to 1 gm. Most of our patients are given either sulfadiazine or sulfathiazole. Inasmuch as we admin~ster the initial dose intravenously, a 5 ·per cent solution of either sodium sulfadiazine or sodium sulfathiazole is used. Although distilled water is generally recommended for the solution, normal saline will serve the purpose equally well. A 5 per cent solution of the drug will amount to 100 cc. by volume if 5 gm. is to be administered. This quantity is given by the drip method beginning with 10 to 15 drops per minute and gradually increasing the rate to 30 drops per minute, allowing about one and one half hours for completing the procedure. If there is any reason why the remedy cannot be injected intravenously and oral administration is not feasible, the drug may be given in a 2.5 per cent solution subcutaneously. We do not favor the use of a stomach tube for introduction of the sulfonamides. With the drug an alkali such as sodium bicarbonate may be used in equal or double amounts, or one sixth molar sodium lactate may be given intravenously. However, it is probably of greater importance to have an adequate intake of fluids. For this latter purpose, 10 per cent glucose or Hartman's solution is appropriate. It is well for the patient to receive from 2000 to 3000 cc. of fluids each twenty-four hours. The amount will depend upon the patient's age. At any convenient time within twelve hours after the initial dose, it is well to determine the blood level for the drug employed. For sulfadiazine, a level of from 10 to 12 mg. per 100 cc. of blood should be expected and this figure approximately maintained. Sometimes the first level will be much higher. Sulfathiazole levels are likely to be low, and it is partly for this reason that sulfathiazole is not generally accepted as an appropriate remedy for meningitis. Sulfathiazole is, in fact; thoroughly efficient, notwithstanding the low blood· levels and
THE ACUTE INFECTIOUS DISEASES
69
the spinal fluid levels that are seldom more than 50 per cent or at most 70 per cent of the blood level. Because of the excellent therapeutic results obtained with sulfathiazole, we are inclined to believe that too much importance is bestowed on blood levels as a guide to dosage. Irrespective of the sulfonamide selected or the blood level reported, our plan of dosage is the same when treating any form of bacterial meningitis. In most cases of meningococcic meningitis, all sulfonamide therapy may ·be discontinued at the end of eight or ten days, and frequently in a lesser time.
Fig.13.-A 14 year old girl admitted in coma to Cook County Hospital. Diagnosis: meningococcemia and meningitis. Massive hemorrhages on arms and similar lesions of lesser size on thighs and buttocks. Also petechiae on face and body. Treated with sulfathiazole and cortate. Photograph about eleven days after onset of illness shows sloughing of skin.
It is well to give adrenal cortical extract to patients with extensive .hemorrhages in the skin, regardless of whether or not it is thought the Waterhouse-Friderichsen syndrome exists. Comparatively few meningitis patients require sedatives, but if such medication becomes necessary a barbiturate, chloral hydrate or paraldehyde maybeadministered. It· is not advisable to give morphine.
70
ARCHIBALD L. HOYNE
Notwithstanding that penicillin seems to be an unnecessary adjunct to the sulfonamide treatment of most cases of meningococcic meningitis, it is distinctly beneficial for certain complications. For endophthalmitis, penicillin may be given both intramuscularly and intravenously or by iontophoresis with remarkably good results. Prophylaxis.-On the basis of reports from military sources during the war, there appears to be no question in regard to the efficiency of the sulfonamides for prophylactic purposes.. Several different plans of dosage were adopted. One consisted of giving a single dose, usually sulfadiazine, of 5 gm. or more. In other instances the drug was administered in 1 gm., doses two or three times a day for a period of three days to a week. Should a case of meningococcic infection develop in one member of a family, it would seem logical to prescribe a sulfonamide; probably 1 gm. three times a day for each contact for a period of three days would be sufficient. Nevertheless, the experience in our contagious disease hospitals regarding this matter is interesting. Within a three-year period, 1943 to 1945 inclusive, nearly 3000 student nurses and probably half as many medical students came in contact with meningococcic patients. No one in either of the two hospitals was given any prophylactic remedy, no one wore face masks, and no one contracted meningitis. OTHER MENINGITIDES
For the most part, what has been said in respect to the therapy of meningococcic meningitis applies to other forms of bacterial meningitis. There are, however, some differences which will be alluded to briefly. Infiuenzal meningitis, which occurs most frequently in those under five years of age and very rarely in adults, still has a high fatality rate. While it is possible to bring about recovery by means of a sulfonamide drug, no patient should be deprived of the specific serum when the latter is obtainable. Type B anti-influenzal rabbit serum developed by Alexander is supplied in 25 mg. ampules. It is well to give at least 50 mg. intravenously and to repeat this dose if there is not some favorable response within twenty-four hours. At the same time, sulfonamide treatment is resorted to and sulfadiazine is often preferred. As a rule, the sulfa treatment should be continued for at least three weeks because there is a strong tendency for the disease to relapse. Eventually streptomycin will probably displace entirely anti-influenzal serum as a therapeutic agent for influenzal meningitis. Present recommendations call for both intrathecal-and intramuscular administration of streptomycin. However, I believe that if large doses-lOO,OOO units (0.1 gm.)-are injected intramuscularly every three hours for a
THE ACUTE INFECTIOUS DISEASES
71
period of five to eight days, intrathecal treatment is not required. We have found that one spinal tap for diagnosis is usually sufficient, but the sulfonamide treatment should be continued for approximately two weeks after completion of streptomycin therapy. Pneumococcic meningitis, regardless of the organism's type, responds well to the sulfonamides. Specific type serum intravenously sometimes seems to be helpful. Penicillin intravenously and intramuscularly is of value. Pencillin intrathecally is likely to clear temporarily the spinal fluid of organisms. Although we have had so many relapses and fatal terminations when penicillin was given intrathecally that we no longer follow this method, we are aware that there have been many favorable reports regarding intrathecal penicillin therapy. Penicillin is particularly. efficient for the treatment of streptococcic and also for staphylococcic meningitis when used intravenously and intramuscularly. In addition, one of the sulfonamides should be given. Tuberculous meningitis is the only one of the meningitides in which some satisfactory response to treatment cannot yet be expected. Streptomycin thus far has not been proved to be efficient in the treatment of tuberculous meningitis. Moreover, this new drug has not yet been used extensively enough to decide the full scope of its value or limitations in other conditions.
L.
HOYNE,
M.D. o
GREAT changes have occurred within recent years in respect to nearly all the acute infectious diseases. Diminished prevalence, fewer serious complications and lower fatality rates have been observed in allnost every section of this country. Something more than progress in methods of immunization and introduction of new forms of therapy has contributed to these improvements in the general state of the public health. Advancement in sanitary science has been a powerful force in the curbing of mortality. Moreover, better homes and a higher scale of living have undoubtedly led to an improved state of nutrition. As a consequence, it seems reasonable to assume that resistance to infection has increased even if pathogenic organisms have not lessened their virulence. But if there has been both an increase of resistance to infection in the general population and also a diminishment in the virulence of disease, then death rates should have declined, even without improved methods of treatment. This last situation seems· to exist in respect to certain diseases, notably smallpox and scarlet fever.
DIPHTHERIA
Diphtheria may be linked with smallpox from the standpoint of prevention, which is the only certain means of eliminating mortality from these diseases. The most expert care will not save the lives of all diphtheria patients. Even in the largest cities, however, remarkable success in stamping out diphtheria is possible when a program of immunization is well planned and energetically directed. Chicago is a good illustration of such an accomplishment. Figures from the Municipal Contagious Disease Hospital serve as an index of declining diphtheria prevalence in that city. In the year 1921, there were 2165 diphtheria patients admitted, in contrast to only twenty-three admissions, with one fatality in 1945. . Chicago's record in respect to diphtheria is particularly cheering at this time when the disease is said to have an increased incidence throughout most of the war-torn world. Even in this country, the United States Public Health Service reports that diphtheria has risen 24' per cent during the first three months of 1946, as compared with the nrst quarter of 1945. From Cook County Hospital, Chicago. o Attending Physician and Chief, Contagious Disease Deparbnent, Cook CoUnty Hospital; Clinical Professor of Pediatrics, University of Chicago School of Medicine. 61
62
ARCHIBALD L. HOYNE
Treatment.-For the treatment of diplltlleria patients, the mere administration of diphtheria antitoxin is not always sufficient. Absolute rest is sometimes equally important because of the danger of myocardial weakness. In serious cases the patient should not even raise his head from the bed. When myocarditis develops it is not likely to be detected prior to the tenth day of disease, and the slightest exertion may then be disastrous. If the patient has been ill without antitoxin for three or more days, we give 10 per cent glucose in distilled water intravenously each twenty-four hours for at least eight days. The amounts usually vary from 500 cc. to 1000 cc., depending on the size of the patient. We believe that if 60,000 units of diphtheria antitoxin will not bring about recovery in a patient, he will seldom get well on double that amount. It is best to inject the antitoxin in the outer muscles of the thigh. Since the adrenals are often dama~ed in severe types of diphtheria, adrenal cortical extract in doses of from 3 cc. to 5 cc. once or twice daily seems to be helpful in some instances. It is also our impression that for severe cases penicillin is a valuable adjunct in treatment. This drug is given in doses of 10,000 to 20,000 units intramuscularly every three hours. As long as a diphtheria patient has a pronounced albuminuria, he should not be regarded as out of danger. The presence or absence of albuminuria is exceedingly dependable as a prognostic guide. Carriers.-PeniciIIin appears to be of value in freeing the nose and throat of diphtheria organisms. For this purpose the drug may be used as a spray, given' in tIle form of a lozenge or injected in tIle muscle. The removal of tonsils and adenoids is likely to be successful when other measures fail. SCARLET FEVER
Scarlet fever provides some of the most difficnlt problems in the field of public health. Whether or not it is controllable depends somewhat upon our conception of the disease. If scarlet fever can occur without a rash, it is not likely to be recognized, and so the individual may convey the infection to others. A patient with a diagnosis of streptococcic sore thrQat is likely to be admitted without question to any general hospital. However, if a rash is observed, the disease is called scarlet fever and the patient is excluded. Nevertheless, the inciting organism may be the same in both instances. A large percentage of an urban population often harbors llemo]ytic streptococci in the nose or throat. This situation in respect to hemolvtic streptococcus carriers among the civilian population llas been reflected in military centers and has sometimes resulted in many cases of scarlet fever. An increase in scarlet fever generally' means an increase in rheumatic fever and, therefore, the former disease becomes of major importance. There is no known method of establishing active immunity against
11IE ACUTE INFECI'IOUS DISEASES
63
streptococcic infections. Consequently, if we acknowledge that scarlet fever can occur without a rash we lnust also admit that there is no agent available for inducing active immunity against this form of scarlet fever. Scarlet fever is far less prevalent and much milder today than only a few years ago and, consequently, deaths are fewer. Treatment.-Serious and even fatal cOlnplications have sometimes followed what appeared to be a mild attack of scarlet fever. Therefore, even though the patient may not seem to be very ill, it is often advisable to administer one of the following therapeutic agents: convalescent scarlet fever serum, scarlet fever antitoxin or penicillin. The sulfonamides are not included here in the list of remedies, because we ,believe they do not influence the toxemia of scarlet fever. Nor do the sulfonamides seem to serve as a prophylactic against complica.. tions, although they are of value in treating certain complications. Convalescent scarlet fever serUln in doses of 20 cc. or more is of value. Because of a number of kno\vn instances in which acute hepatitis followed the injection of pooled human serum,· however, there are now some \vhooppose the use of human convalescent scarlet fever serum. Convalescent scarlet fever serum may be given intramuscularly or intravenously at any stage of the disease but preferably early. Scarlet fever antitoxin in doses of 9000 units consists of only about 5 cc. or less by volume. It is now so highly concentrated and re.. fined that unpleasant reactions are rare. To be effective, it should be given before the rash has disappeared, whicll means, as a rule, before the third day of eruption. It should be injected in the muscle. It is not recommended for the ·treatment of complications. Our experience during the last year and a half with the use of penicillin suggests that this new drug is a useful remedy for scarlet fever. TIle intramuscular injection required for its greatest effective'ness is, however, a disadvantage in adlninistration. Treatment consists in the injection of the drug in 10,000 to 15,000 unit doses every tllree
hours.
It is stated that penicillin, when given in adequate dosage, will elitninate hemolytic stre!Jtococci from nose and throat within seven days. When used orally or in the form of a spray, penicillin is not so effective for eradication of hemolytic streptococci. Lately, penicillin in peanut oil has been made available. It is claimed that when tllis preparation is injected, in 300,000 unit doses intramuscularly about every three days it is as effective as. when smaller doses are injected every three hours. We have not yet had sufficient experience ,vitll the oil preparations to judge their usefulness. There are some who strenuously object to the use of pencillin in peanut oil on the grounds that sensitization is not infrequent and that asthmatic attacks are produced.
64
ARCHlBALD L. HOYNE
.
IlEASLES
Mter the first six months of life susceptibility to measles is practically universal at any age for those who have not had the disease. Before six months measles is uncommon, and under four months the disease is rare. It may be assumed that one attack of measles confers a lifetime immunity. There is no known method for establishing an artificial active immunity. Passive immunity may be accomplished in one of several ways: Convalescent measles serum in doses of 7.5 to 10 cc.; immune globulin (placental extract) 2 cc. to 5 cc., or the newer preparation developed through the processing of blood by the Red Cross, garrl,rna globulin, 2.5 cc. to 5 cc. To be effective for prevention, anyone of these substances should be given by the intramuscular route within three days of exposure. If it is desired to modify an attack of measles, five to six days should be allowed to elapse after exposure before making the injection. For prevention, sometimes two doses of the material are given: the first dose as soon after exposure as possible and a second dose five to six days later. It must be remembered this is merely a temporary protection that may endure for only two or three weeks. If the patient has a modified or attenuated attack of measles, immunity is likely to be permanent, although this is sometimes questioned. Treatment.-Measles is a respiratory disease, and this fact should be kept in mind. Good ventilation is a requirement for proper care and undoubtedly lessens the possibility of a complicating bronchopneumonia. The value of amidopyrine, to which we were probably the first to call attention many years ago, ·has not been altered in my opinion. This drug may be given in doses of 1 grain (0.065 gm.) per year of age up to 5 grains (0.33 gm.), which was our original maximum. It is administered from three to four times daily for a period of three to four days and is best prescribed in a vehicle because in tablet form it occasionally causes nausea. I have never seen any harm result from the use of this drug when given in the manner described. Amidopyrine reduces fever, lessens cough, and apparently diminishes complications. It is mucll more effective than acetylsalicylic acid. Convalescent measles serum even in large doses is of doubtful value, and the use of gamma globulin for treatment does not seem to be justified. For patients with bronchopneumonia nothing is superior to the oxygen tent. Sulfadiazine, sulfathiazole and penicillin are beneficial. Measles Encephalitis.-It has been estimated that encephalitis develops in about one in one thousand cases of measles. This complication seems to be much more frequent than twenty years ago. Measles encephalitis when present generally occurs before the rash has disappeared, usually on the fourth or fifth day of the eruption. The patient's future is always in doubt. More than one third of our
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patients have seemed to make a complete recovery; sometimes, as many as one third have died, and others were left with permanent mental defects. The spinal fluid findings are not of diagnostic or prognostic significance. The fluid has a normal appearance and the cell count may be normal or increased, sometimes to 200 or more cells, which are nearly all lymphocytes. Treatment.-Treatment of measles encephalitis often includes the use of an oxygen tent. The administration of 10 per cent glucose intravenously by the drip method is of value. We have frequently given also 200 cc. or more of measles convalescent serum intravenously. Whether this latter procedure actually has any specific value is doubtful. Plasma as a substitute for convalescent serum when given in equal volume is probably as helpful. Whole blood transfusions are undoubtedly beneficial in some cases. Feeding by gavage may be necessary. Bronchopneumonia may terminate the patient's existence and, therefore, one of the sulfonamides or penicillin or both are often prescribed with the hope of forestalling tllis final complication. After the temperature has returned to normal we have given some of our patients benzedrine sulfate in 5 mg. doses once or twice a day. A few patients seemed much more alert after this treatment. WHOOPING COUGH
In recent years pertussis has accounted for more deaths than nearly all the other common contagious diseases combined. It is particularly fatal during tIle first year of life. There is now available a number of vaccines for the prevention of whooping cough. Sauer's vaccine is undoubtedly the most popular in the Midwest. It is administered subcutaneously in three doses of 1, 2, and 3 cc. each at monthly intervals. Since each cubic centimeter contains 15 billion killed organisms (Hemophilus pertussis), the entire immunizing dose is 90 billion organisms. Generally, it is recommended that antipertussis inoculations should not be given before the second half year of life. Eight months is often the age selected for this purpose. The reason for not making these injections early is because of the lack of antigenic response during the first few months of the baby's existence. However, it requires about four Inonths to build up immunity, and if immunization is not undertaken prior to eight months, protection cannot be secured before one year of age. Consequently, those in early infancy who are in greatest need of a safeguard from pertussis are denied this benefit. In 1940, the Committee of the American Academy of Pediatrics for the State of Illinois recommended in a pamphlet distributed by the lllinois State Department of Health that whooping cough immunization be undertaken at three to four months of age. This advice was
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ARCHIBALD· L. HOYNE
given on the theory .that. everi '"if 'complete protection was not secured, a modified attack might occur:u whooping cough was acquired, thus reducing the fatality rate, which is highest for those under one year
of By age.me'ans 'f ,. f·· t·· ft· · h 0 a serIes 0 . InJec Ions 0 per USSIS vaCCIne, t e pregnant woman is sometimes treated for the purpose of transmitting immunity to the unborn child. Success has been claimed by resorting to this method. Pertussis vaccine may be administered alone or in combination with either diphtheria alum-precipitated toxoid or tetanus alum-precipitated toxoid or both. Human hyperimrnune pertussis serum may be us.ed for passive immunity. There is no\v' available a 11ighly concentrated human hyperimmune serum which is sold under the name of Hypertussis. This product appears to 'be of undoubted value. It is injected intramuscularly in doses of from 2.5 to 5 cc. Treatment.-Good ventilation, expert nursing, and proper feeding are the prime requisites for the average case of whooping cough. Regardless of age, it is better to give nourishment in small amounts on many occasions than to give large quantities of food at greater intervals. If a baby suffers a paroxysm after takin~ its bottle, the contents of the stomach are likely to be evacuated. Under such circum.. stances about fifteen minutes are allowed to elapse and another bottle contaIning the prescribed formula is provided. It is very necessary that proper nutrition shall be sustained. Patients with cyanosis or convulsions should be placed in an oxygen tent and may benefit from blood transfusions or hyperimmune serum.' Hyperimmune rabbit serum has been available for some time but the concentrated human hyperimmune serum is a newer product. For infants under one year' of age, concentrated human hyperimmune pertussis serum maybe given intramuscularly in doses of 2.5 cc. and repeated if necessary. Patients of any age should have the services of an oxygen tent when bronchopneumonia is present. Carbon dioxide has also been used, but we now believe this is unnecessary. Sulfathiazole or sulfadiazine is of value, and on some occasions penicil.. lin has seemed to be definitely worth 'Yhile when there are mixed infections. Although it has been reported that streptomycin is effective for the treatment of pertussis, the dru~ has not been sufficiently plentiful to permit many to pass on its merits. In hospital practice in Chicago we rarely resort to sedatives and prefer not to do so. However, if sedation is deemed necessary, chloral hydrate 5 to 10 grains (0.33 to 0.65 gm.) may be given by rectum or sometimes 3~ to ~ grains (0.032 to 0.05 gm.) of seconal in a similar manner. For patients in the home, luminal in doses of 1" to 3 grains (0.1 to 0.2 gm.) may prove to be very satisfactory.
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MENINGOCOCCIC MENINGITIS
Undoubtedly the greatest progress in the treatment of acute infectious diseases in recent years pertains to the meningitides. In the past, practically all forms of bacterial meningitis were usually 100 per cent fatal with the exception of the meningococcic variety. In the case of the latter, although there had been a specific antiserum in common use since 1907, the results were far from satisfactory. Gover and Jackson state that the case fatality rate of cerebrospinal meningitis was 55 per cent in 1980 for the country as a whole, and that it was 39 per cent in 1940. Prior to 1940, the year sulfonamides came into general use, the accepted method of administering serum was by the intrathecal route. In addition, frequent drainage of cerebrospinal fluid to relieve intracranial pressure was regarded as imperative. For these two purposes, daily lumbar punctures were considered a necessity. In some eastern hospitals this procedure was carried out as often as every six hours during the first few days. Even when Schwentker first reported the use of sulfanilamide for meningococcic meningitis, he injected the drug intrathecally. Soon after beginning our clinical trial of Ferry's newly developed meningococcus antitoxin at the Cook County Hospital in 1934, we discontinued all intrathecal treatment in favor of the intravenous route. We also abandoned the long existing theory that repeated withdrawals of spinal fluid were necessary to relieve intracranial pressure. Furthermore, it was found that patients made excellent recoveries without any spinal puncture. The clinical diagnosis was confirmed by either a positive blood culture for meningococci or by a positive smear from petechiae when the latter were present. During the few years of exclusive intravenous therapy at the Cook County Contagious Disease Hospital and also at Municipal Contagious Disease Hospital, we sometimes had lower fatality rates for meningococcic meningitis than we have ever had since the introduction of the sulfonamides. Much of our success was attributed not merely to the fact that large doses of serum were administered intravenously but because no irritating substance was injected intrathecally. Therefore, it is my opinion that a share of the remarkable efficiency of sulfonamide therapy should be attributed to the omission of intrathecal serum. Unfortunately, with the coming of penicillin, after intrathecal therapy had at last been reluctantly discarded by many, there has been a disposition to resort again to intraspinal treatment. Yet, even those who advocate the administration of penicillin intrathecally admit the disadvantage of the method and confess that adhesions, blocks and other complications sometimes occur. We continue to believe that intrathecal therapy is not only unnecessary for any kind of meningitis but that it may be actually harmful.
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ARCHIBALD L. HOYNE
Treatment.-The management of meningococcic infections may be as follows: If petechiae are present, scarify one of the lesions, make a smear, stain and examine for gram-negative diplococci. Regardless of whether organisms are found in smear or not, always obtain blood for culture. The patient may have meningococcemia without clinical evidence of meningitis. If smear or blood culture is positive, a spinal puncture is not necessary. If the patient has no petechiae, a lumbar puncture is essential for examination of spinal fluid and prompt laboratory diagnosis. Any of the principal sulfonamides may bring about recovery. Sulfadiazine, sulfathiazole and sulfamerazine are the chief ones for consideration. For practical purposes it is not obligatory to determine dosage on the basis of patients' weight but rather on the severity of the disease. For children under five years our initial dose of the drug selected is usually from 2 to 3 gm., followed every four hours by from 0.5 to 1 gm. Most of our patients are given either sulfadiazine or sulfathiazole. Inasmuch as we admin~ster the initial dose intravenously, a 5 ·per cent solution of either sodium sulfadiazine or sodium sulfathiazole is used. Although distilled water is generally recommended for the solution, normal saline will serve the purpose equally well. A 5 per cent solution of the drug will amount to 100 cc. by volume if 5 gm. is to be administered. This quantity is given by the drip method beginning with 10 to 15 drops per minute and gradually increasing the rate to 30 drops per minute, allowing about one and one half hours for completing the procedure. If there is any reason why the remedy cannot be injected intravenously and oral administration is not feasible, the drug may be given in a 2.5 per cent solution subcutaneously. We do not favor the use of a stomach tube for introduction of the sulfonamides. With the drug an alkali such as sodium bicarbonate may be used in equal or double amounts, or one sixth molar sodium lactate may be given intravenously. However, it is probably of greater importance to have an adequate intake of fluids. For this latter purpose, 10 per cent glucose or Hartman's solution is appropriate. It is well for the patient to receive from 2000 to 3000 cc. of fluids each twenty-four hours. The amount will depend upon the patient's age. At any convenient time within twelve hours after the initial dose, it is well to determine the blood level for the drug employed. For sulfadiazine, a level of from 10 to 12 mg. per 100 cc. of blood should be expected and this figure approximately maintained. Sometimes the first level will be much higher. Sulfathiazole levels are likely to be low, and it is partly for this reason that sulfathiazole is not generally accepted as an appropriate remedy for meningitis. Sulfathiazole is, in fact; thoroughly efficient, notwithstanding the low blood· levels and
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the spinal fluid levels that are seldom more than 50 per cent or at most 70 per cent of the blood level. Because of the excellent therapeutic results obtained with sulfathiazole, we are inclined to believe that too much importance is bestowed on blood levels as a guide to dosage. Irrespective of the sulfonamide selected or the blood level reported, our plan of dosage is the same when treating any form of bacterial meningitis. In most cases of meningococcic meningitis, all sulfonamide therapy may ·be discontinued at the end of eight or ten days, and frequently in a lesser time.
Fig.13.-A 14 year old girl admitted in coma to Cook County Hospital. Diagnosis: meningococcemia and meningitis. Massive hemorrhages on arms and similar lesions of lesser size on thighs and buttocks. Also petechiae on face and body. Treated with sulfathiazole and cortate. Photograph about eleven days after onset of illness shows sloughing of skin.
It is well to give adrenal cortical extract to patients with extensive .hemorrhages in the skin, regardless of whether or not it is thought the Waterhouse-Friderichsen syndrome exists. Comparatively few meningitis patients require sedatives, but if such medication becomes necessary a barbiturate, chloral hydrate or paraldehyde maybeadministered. It· is not advisable to give morphine.
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ARCHIBALD L. HOYNE
Notwithstanding that penicillin seems to be an unnecessary adjunct to the sulfonamide treatment of most cases of meningococcic meningitis, it is distinctly beneficial for certain complications. For endophthalmitis, penicillin may be given both intramuscularly and intravenously or by iontophoresis with remarkably good results. Prophylaxis.-On the basis of reports from military sources during the war, there appears to be no question in regard to the efficiency of the sulfonamides for prophylactic purposes.. Several different plans of dosage were adopted. One consisted of giving a single dose, usually sulfadiazine, of 5 gm. or more. In other instances the drug was administered in 1 gm., doses two or three times a day for a period of three days to a week. Should a case of meningococcic infection develop in one member of a family, it would seem logical to prescribe a sulfonamide; probably 1 gm. three times a day for each contact for a period of three days would be sufficient. Nevertheless, the experience in our contagious disease hospitals regarding this matter is interesting. Within a three-year period, 1943 to 1945 inclusive, nearly 3000 student nurses and probably half as many medical students came in contact with meningococcic patients. No one in either of the two hospitals was given any prophylactic remedy, no one wore face masks, and no one contracted meningitis. OTHER MENINGITIDES
For the most part, what has been said in respect to the therapy of meningococcic meningitis applies to other forms of bacterial meningitis. There are, however, some differences which will be alluded to briefly. Infiuenzal meningitis, which occurs most frequently in those under five years of age and very rarely in adults, still has a high fatality rate. While it is possible to bring about recovery by means of a sulfonamide drug, no patient should be deprived of the specific serum when the latter is obtainable. Type B anti-influenzal rabbit serum developed by Alexander is supplied in 25 mg. ampules. It is well to give at least 50 mg. intravenously and to repeat this dose if there is not some favorable response within twenty-four hours. At the same time, sulfonamide treatment is resorted to and sulfadiazine is often preferred. As a rule, the sulfa treatment should be continued for at least three weeks because there is a strong tendency for the disease to relapse. Eventually streptomycin will probably displace entirely anti-influenzal serum as a therapeutic agent for influenzal meningitis. Present recommendations call for both intrathecal-and intramuscular administration of streptomycin. However, I believe that if large doses-lOO,OOO units (0.1 gm.)-are injected intramuscularly every three hours for a
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period of five to eight days, intrathecal treatment is not required. We have found that one spinal tap for diagnosis is usually sufficient, but the sulfonamide treatment should be continued for approximately two weeks after completion of streptomycin therapy. Pneumococcic meningitis, regardless of the organism's type, responds well to the sulfonamides. Specific type serum intravenously sometimes seems to be helpful. Penicillin intravenously and intramuscularly is of value. Pencillin intrathecally is likely to clear temporarily the spinal fluid of organisms. Although we have had so many relapses and fatal terminations when penicillin was given intrathecally that we no longer follow this method, we are aware that there have been many favorable reports regarding intrathecal penicillin therapy. Penicillin is particularly. efficient for the treatment of streptococcic and also for staphylococcic meningitis when used intravenously and intramuscularly. In addition, one of the sulfonamides should be given. Tuberculous meningitis is the only one of the meningitides in which some satisfactory response to treatment cannot yet be expected. Streptomycin thus far has not been proved to be efficient in the treatment of tuberculous meningitis. Moreover, this new drug has not yet been used extensively enough to decide the full scope of its value or limitations in other conditions.