Experience with Isoniazid Prophylaxis in a Large City Health Department* LEONARD
I.
STEINFELD, M.D.** AND SAMUEL CLIVE COHEN, M.D., F.C.C.P.t
Boston, Massachusetts
T
ing that isoniazid is effective in at least one and possibly two of the situations described.
INTRODUCTION HE ROLE OF ISONIAZID PROPHYLAXIS
in the quest for tuberculosis control continues in the forefront of present investigator thinking. To some it is the panacea long awaited, to others it is of questionable value, 1 for most it is a logical and apparently effective concept which remains to be conclusively proved by mass clinical trial, but the idea of isoniazid prophylaxis is a many faceted concept which should be understood by all concerned. To the child with a negative skin test, apparently uninfected, living in the household of a parent with active disease refusing hospitalization, we administer isoniazid to prevent the e~tablishment of infection. For a sibling in the same household found to have a positive skin test and negative chest x-ray film, we give isoniazid with the hope of thwarting the progression to clinically apparent disease. For the sibling again in the same household with x-ray evidence of primary disease, positive skin reaction, apparently inactive after being followed for a period of time, we may start a program of isoniazid prophylaxis in the hope that reactivation of the focus of infection in the future will be prevented. Isoniazid prophylaxis may play a successful role in one, two or all of the described situations. Evidence in support of or against each of these situations remains in its infant stage of accumulation, but confinned skeptics should be fully aware of the manifold situations implied in the term isoniazid prophylaxis. Furthermore, evidence is slowly accumulat-
HISTORY
·From the Tuberculosis Clinics, City of Boston, Department of Health and Hospitals. Presented at the Interim Clinical Meeting, American College of Chest Physicians, Las Vegas, November 26-28, 1966. ··Surgeon U. S. P. H. S., Communicable Disease Center, 'Tuberculosis Branch. tDirector of Tuberculosis Clinics, City of Boston, Department of Health and Hospitals.
The largest controlled trials in the prophylactic use of isoniazid are being conducted by the United States Public Health Service and these have already provided indications as to the effectiveness of isoniazid prophylaxis.! Among several thousand children with primary tuberculosis, half of whom were placed on isoniazid and haH on a placebo group, 31 children of the placebo group and only two in the isoniazid group developed extrapulmonary complications of their primary disease. Among contacts of active cases divided in a similar manner into placebo and isoniazid groups, 103 cases of tuberculosis were discovered in the placebo group during the medication year versus 26 in the isoniazid group. From these and several other Public Health Service trials, it has been shown that isoniazid prophylaxis can substantially reduce the number of cases of tuberculosis appearing while participants are on medication. Ferebee and associates' have projected from these trials that the use of isoniazid prophylaxis can be expected to reduce by three-fourths the number of tuberculosis cases expected in these selected populations. Perhaps the most informative of the trials with information available concerning isoniazid prophylaxis is Ferebee and Mount's' study of 25,033 household contacts of new active cases divided into placebo and isoniazid prophylaxis groups. This study showed that during the medication year: 1) isoniazid had no effect on the number of primary cases detected among those infected (positive skin test) when therapy began; 2) isoniazid is quite
406
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EXPERIENCE WITH ISONIAZID PROPHYLAXIS
effective in preventing the appearance of primary disease in those uninfected (negative skin test) at the beginning of therapy; 3) isoniazid is very effective in preventing extrapulmonary tuberculosis among household contacts; 4) isoniazid will significantly effect the number of cases of active pulmonary tuberculosis appearing. AIl indications now point to the effectiveness of isoniazid prophylaxis in the prevention of primary disease for the uninfected and the prevention of pulmonary and extrapulmonary disease in both infected and uninfected persons. The problem of reducing the likelihood of disease in years to come by treating the infected person is the most difficult question to answer presently. The indications of a lasting effect of isoniazid prophylaxis, however, are also suggested by the Public Health Service trials. Ferebee et af reported that after the medication year, among children with primary tuberculosis, there were eight extrapulmonary complications among untreated persons versus four in the isoniazid therapy group. Furthermore, in her study of household contacts, 18 cases of tuberculosis have been reported in the isoniazid treated group versus 27 cases in the placebo group fol-
lowing the medication year. Finally, among mental patients, 15 casts have been uncovered in those isoniazid treated versus 30 on placebo, after the medication year. These statistics do suggest that isoniazid prophylaxis may have a lasting effect, but are only fragmentary and we await longer tenn followup from these investigators which should be soon in coming. METHODS
In 1958, the Tuberculosis Clinics of the Boston Health Department first began exploring the idea of isoniazid prophylaxis in a systematic manner, but reserved its use to selected situations, such as in both positive and negative reactors living in a household with an active case of tuberculosis or in positive reacting children with a high suspicion of recent conversion. By 1960, this program had been expanded to include all positive reacting children, no matter how discovered, and the next year an active mass school skin testing program in the city of Boston was started and has continued each year to the present time, adding considerable numbers of positive reacting children to our program. At the inception of our prophylaxis program, the aim of this course of therapy
Distribution of Skin Test Sizes
140 120 100
Number of Patients 80 60 40
en ~
I
0
U)
~
20
~
~
~
-t ~
0
LI)
N
~
Skin Test Induration
l1ID FIGURE
1
Diseases of the Chest
STEINFELD AND COHEN
TABLE I-TOTAL YEARS FOLLOW Up IN PUBERTY AOE GROUPS
Age
No. Patients
12 13 14
31 49 62 43 24
15 16
Ave~ Total
Yean Oblerved 3.14 2.84 2.42 2.30 2.39
was to prevent near tenn disease in both infected and uninfected persons. As the pro g ram expanded, our thinking also broadened and we were also of the belief that a course of isoniazid prophylaxis might affect dormant tuberculous foci and thus decrease considerably the risk of reactivation in future years in infected individuals. About five years ago it was suggested that if one year of therapy had an advantageous effect on dormant foci of infection, two years of therapy would have an even greater effect and it was then decided to treat all persons in our prophylaxis program for two years. This policy remains in effect today in our clinics, although selected patients may have their medication discontinued after lesser periods of time because of particular extenuating circumstances. The determination of positive reacting patients in our clinics has always been made by using the Mantoux Test, utilizing old tuberculin at 5 OT units strength. Several years ago we adopted the parameter of 10 mm of induration or greater as indicative of a positive reacting subject. This level of positivity was adopted because: t) it had been our experience that the vast majority of our patients reacting to our TABLE 2-PaOBABLE SOURCES OF INFECTION
Source Case
Father Mother Grandparent Sibling Friend Aunt-Uncle Other Relative Husband-Wife Unknown
Per Cent Patients Linked to This Source 18
13 7 7 7 8 1 1 38
Mantoux test had measurements of 10 mm or more induration; 2) we encounter atypical mycobacterial infections very infrequently; 3) those reacting nonspecifically to our Mantoux test generally had reactions of less than 5 mm induration; and finally, 4) any reactors of less than 10 mm are retested in three months. All those persons in our isoniazid prophylaxis program (99 per cen t are less than 20 years old, as it has been our policy to exclude those over 20 years of age except in un us u a I circumstances) were given isoniazid at a dosage of approximately 10 mgjkg to a maximum of 300 mg daily. Pyridoxine 25 mg daily was added in rare instances when its use was suggested by patient complaints. Patients were followed at intelVals of three months and thus ideally saw a physician four times a year. X-ray films were taken at yearly intervals. We presently have approximately 1,000 patients who are participating in this program or have completed their course of therapy. This study is an analysis of 442 patients who have finished their course of therapy and are still being followed up in our clinics. In our prophylaxis program we also include those with x-ray evidence of primary disease in whom no evidence of activity is suspected, nor found, e.g., serial x-ray changes, sputum analysis and whom we are treating for the suspected lasting effect of isoniazid prophylaxis. RESULTS
Sex: Of the 442 patients in our study, 51 per cent were males and 49 per cent females. Race: Distributing the group by race, we found Caucasians comprised 67 per cent of the total, Negroes 26 per cent and TABLE 3-DURATION OF THERAPY
Months on Therapy
No. Patients
12-17 18-23 24 or more
44 49 349
PerCent Patients 10 11 79
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EXPERIENCE WITH ISONIAZID PROPHYLAXIS
Orientals 7 per cent. Although exact figures were not available, we are certain that the incidence of tuberculosis in the Negro population is much greater than the incidence in the white population despite the fact that whites make up the majority of the total reported cases. Age Therapy Began: Only 1 per cent of our study population was over the age of 20. The majority of the patients (47 per cent) fell in the 12 to 16 age group broadly associated with the stage of puberty and well known as that period of increasing risk of acquiring pulmonary tuberculosis between the safety of late childhood and the high rate in young childhood. Seventeen per cent of the group were five years old or less, also a period of greater risk of developing tuberculosis. Total Years Observed: Analysis of the total years under observation of these patients revealed that 45 per cent have been followed-up for three or more years, 97 per cent of the group have been followedup for at least two years, 5 per cent for five or more years. Table 1 correlates the average total years of follow-up with age groups within the period of puberty, a relatively higher risk group in terms of the appearance of tuberculosis. Relationship of Probable Source Case to Prophylactic Patient: Table 2 shows the relationship of the probable source of infection to our prophylactic patients. In 38 per cent of our group, the source of infection was not discernible. Parents were identified as source cases in 31 per cent of the group. Grandparents, siblings, friends and aunts or uncles were closely grouped as the second most common source of infection. Total Months of Therapy: Table 3 disTABLE
4-o.uo
Symptoms Neuropathy
Chilb,
na~~ voDrldng Skin eruption General irritability Insomnia
Total
tributes our study population by the total number of months on isoniazid therapy and shows that 79 per cent of the group received two or more years of drug treatment. Five per cent of our group received isoniazid for three or more years usually because of the presence of an active recalcitrant case in the household. Regularity of Attendance: We have always been of the opinion that regularity in keeping scheduled clinic appointments is the best indicator of the reliability of a patient's drug consumption. Patients in our clinics are expected to return at threemonth intervals to be examined by a clinic physician. Drug supplies are issued for six-week or three-month periods depending on the physician's evaluation of the patient's potential reliability in a program requiring long-tenn supervision. Patients failing to keep scheduled clinic appointments are amumed to be no longer taking their medications. Eighty-one per cent of our group were found to have regular attendance while under therapy, never lapsing from under supervision. Fifty-three patients (12 per cent) were classified as "somewhat irregular" in attendance, having missed one but no more than two visits; 7 per cent (32) of the group were very irregular in attendance, missing more than two visits or lapsing from under therapy for a period of six months or greater. Drugs and Reactions to Drugs: Nine cases (2 per cent) of true or suspected reactions to isoniazid therapy were recorded. Table 4 describes these in detail. Only 7 of the 442 patients in this group received pyridoxine. In four of these patients, pyridoxine therapy was initiated because of vague suggestions of symptomatology. Chest X-Ray Film Evaluation: Eightythree per cent (365) of the patients in this
REACTIONS
No. Cases
3 2 2 1 1
9
TABLE 5-COMPARISON OF SKIN TEST SIZE WITH X-RAy FINDINGS
Positive Reactors with
Number
Median Skin Test Size
Negative x-ray findings X-ray evidence primary disease
320
15mm
77
20mm
4 10
Diseases of the Chest
STEINFELD AND COHEN
study had initial chest x-ray films interpreted as having no significant findings. Seventeen per cent ( 77) had x-ray evidence of primary disease with no suspicion of activity, e.g., because of the presence of calcified complexes and by history. Repeat chest x-ray films while these patients were under supervision, taken at least one year later, revealed an additional 19 with x-ray evidence of calcified presumably inactive primary disease making a total of 96 or 22 per cent showing evidence of primary disease on chest x-ray film while under supervision. In five of the original 77 interpreted as probable primary inactive cases by chest x-ray examination, there was evidence of diminishing activity on followup x-ray films raising the suspicion of primary active disease in these cases. Size of Skin Test: Figure 1 graphically portrays the distribution of the size of skin tests in our population. Peaks around the regular intervals of 5, between 10 and 30 mm, are partly attributable to the measuring device used for Mantoux reading which has circles of 5, 10 and 20 mm that can be placed upon the arm being measured. The median skin test size in the group as a whole falls at the 18 mm level. There is accumulating evidence supporting the direct relationship of the size of the initial tuberculin reaction with the risk of developing clinical disease. Since we offer prophylaxis to those with or without x-ray evidence of disease, and the fact that we have never seen a case of tuberculosis occurring in our prophylactic group, the only correlation we could draw wa~, in retrospect, a comparison of skin test sizes of those with negative x-ray films versus those with primary disease by x-ray examination. Table 5 compares the median in skin test sizes of the two groups after excluding those with negative skin reactions and positives whose exact skin test size was not known. There appears to be a correlation of increasing skin test size with the likelihood of the appearance of primary disease by chest x-ray examination.
Appearance of Tuberculosis: To this date, we have not seen the appearance or reappearance of clinically active tuberculosis in any patient participating in our isoniazid prophylaxis program. Ferebee and Mount' report that among 12,439 household contacts receiving isoniazid prophylaxis, during the medication year, 22 cases of active primary disease were diagnosed, four cases of extrapulmonary tuberculosis and 14 cases of pulmonary tuberculosis. Furthennore, they have reported an additional 17 cases appearing shortly after the medication year, but these statistics are still being accumulated. It is interesting that we have yet to report the appearance of a case of tuberculosis in our group in either the medication years or afterwards, even considering the smaller size of our study group. Among the differences in our program, as compared to the Public Health Service trials which can be cited are: (1) isoniazid dosage of 10 mgjkg which is approximately twice their dosage; and ( 2) our policy of two years of therapy for the great majority of our patients. Weare presently following an additional 600 patients who are still in their medication years and have likewise not observed a case of clinical tuberculosis in this group. There is no doubt in our minds as to the effectiveness of isoniazid prophylaxis from our experience which has apparently been even more favorable than that of other investigators as reported in the literature. It has reduced the expected incidence of tuberculosis among patients while taking the pills. There has also been the suggestion of a lasting effectiveness in that we have not seen reactivations of the disease in subsequent years. We strongly support the use of isoniazid prophylaxis as an important adjunct to our efforts to control tuberculosis. SUMMARY
Isoniazid prophylaxis therapy has been used in over 1,000 patients at the Tuberculosis Clinics of the Boston Health Department during the past seven years. Four
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EXPERIENCE WITH ISONIAZID PROPHYLAXIS
hundred forty-two patients who have completed their course of therapy and-· have been followed up for an average of over three years are reviewed. The majority of patients received two years of daily isoniazid therapy at a dosage of 10 mgjkg. To this date, no case of clinically active tuberculosis has appeared among the 1,000 patients under observation. This experience strongly suggests both a short term prophylactic effect and a longer term lasting effectiveness of isoniazid prophylaxis. RESUMEN
La profilaxis con la isoniazida ha sido practicada en mas de 1000 sujetos en los dispensarios del Departamento de Salud Publica de Boston durante los ultimos siete afios. Hemos revisado 442 pacientes que completaron este tipo de tratamiento y fueron observados por mas de tres afios. La mayorla recibieron isoniazida por dos aDOS. Hasta la fecha no ha aparecido ningun caso de actividad tuberculosa entre los mil casos en observaci6n. Este resultado indica que se ha obtenido un efecto profilactico inmediato y duradero con la isoniazida. ZUSAMMENFASSUNG
Therapie mit Isoniazid-Prophylaxe gelangte zur Anwendung bei mehr als 1000 Patienten an der
4 11
Tuberkulose-Ambulanz des Bostoner Gesundheitsamtes im Verlaff der letzten 7 Jahre. Es wurden 442 Patienten, die ihre Behandlung abgeschlossen hatten und flir eine durchschnittliche Zeitspanne von mehr als 3 Jahren nachbeobachtet worden waren, erneut iiberpriift. Die Mehrzahl der Patienten erhielt wihrend 2 Jahren taglich INH in einer Dosierung von 100 mg/kg Korpergewicht. Bis zu m gegenwirtigen Zeitpunkt is kein einziger Fall einer klinisch aktiven Tuberkulose in Erscheinung getreten bei den 1000 Patienten, die un t e r laufender Beobachtung standen. Diese Erfahrung laPt die Vermutung sehr wahrscheinlich werden, daP e in e Isoniazid-Prophylaxe sowohl eine prophylaktische Bedeutung als Kurzzeit-Behandlung hat, aber auch eine Wirksamkeit, die sich fiber eine tangere Zeit erstreckt. REFERENCES
1 M YERS~ J. A.: "The natural history of tuberculosis in the human body," JAMA~ 194: 1086,
2
1965.
FEREBEE, S. H., MOUNT~ F. W. AND COMSTOCIt, G. W.: "The use of chemotherapy as
a prophylactic measure in tuberculosis," Ann.
N. Y. A. cad. Sci., 106: 151, 1963. 3 FEREBEE, S. H. AND MOUNT, F. W.: "Tuber-
culosis morbidity in a controlled trial of the prophylactic use of isoniazid among household contacts," Ame,. Rev. Res/J. Dis.~ 85: 490, 1962.
For reprints, please write: Dr. Samuel Clive Cohen,
57 East Concord, Boston 02118.
NONTUBERCULOUS CAVITIES IN PNEUMOCONIOSIS Among 108 patients treated at the Medical Academy Hospital In Kracow for massive fibrotic pneumoconiosis, sputum negative, in six coal miners, cavities In massive fibrosis were observed. All patients occasIonally pectorated profuse, black, coaltar-Ilke sputum. In all of the cases, pulmonary fibrosis was far advanced at the time of detection. In cases of less exteDalve fibrosis, not exceeding half of both lung zones, administration of antibiotics and cardiac
drugs resulted In Improvement. Two patients died In the hospital because of circulatory failure: necropsy did not reveal any tuberculous lesion. The manifestations constituting the syndrome of sterile cavity In coal miners with massive pneumoconiosis are discussed In detan. S.: "Nontubercu1ous 'Sterile' cavities in pneumoconiosis with massive tumor-like shadows in coal minen," G,..zliell. 33: 1307, 1966. NIZlNSKI,
AMYL NITRITE IN SUBAORTIC STENOSIS The effects of amyl nItrite inhalation were oblerved In 12 patients with aortic valve stenosis and five patients with muscular subaortlc stenosis durIng left heart catheterization. In aortic valve stenOils, the left ventricular systollc pressure always fell. although less than the brachial arterial pressure, and the transaortlc systollc pressure gradient rose by an average of 25 per cent due to Increase In left ventricular ejection rate. In muscular subaortic stenosis, the left ventricular pressure always remained the same or rose despite a marked fall In brachial arterial pressure, and the averaae Increase
In transaortlc systollc pressure gradient was more than fourfold. This etlect was usoclated with a slgnl1lcant Increase In the degree of ouUlow tract obstruction. The authors belleve that Inhalation of amyl nitrite Is superior to Infusion of Isoproterenol as a provocative test for muscular subaortlc stenosis during cardiac catheterization and Is probably the most potent stimulus available for this purpose. E. W. AND POWKES, W. C.: "Effects of amyl nitrite in aortic valvular and muscular subaortie stenosis," eire.Jlllio II , 33:383, 1966.
HANCOCK,