The treatment of primary tuberculosis in infancy

T H E TRE2~TIV[ENT OF PRIMARY TUBERCULOSIS IN INFANCY ~V~At~YETHEL

MEYER, M.D., GARDNERM I D D L E B R O O K , ARTHUR ROBINS0N, M.D. DENVER, COLO.

H I S paper is prompted by our

T conviction that the handling of the

infant with primary tuberculosis has not received sufficient attention in the pediatric literature, and that there is no clear-cut plan for the treatment of children in this age group by the practicing pediatrician. For the purposes of this paper, we will define an infant as a child 12 months or younger, although we are fairly sure that the following statements apply equally well to infants 1 to 2 years of age.*" In general, primary tuberculosis has not been considered to have a serious immediate prognosis in childhood. However, tuberculosis occuring in infancy has very serious consequences. This is attested to by the fact that the death rate from tuberculosis per 100,000 estimated infected persons was 4,920 for infants aged 0 to 12 months, 18 for children aged 5 to 9 years, and 82 for all age groups in 1940 in the United States. 1 It is interesting t o digress briefly from the main topic to note that the declining mortality from tuberculosis started long before 1900 and repreF r o m t h e N a t i o n a l J e w i s h I-!ospital a n d the U n i v e r s i t y of Colorado School of l~edicine. Aided by the United States Public Health S e r v i c e G r a n t E - 1 2 3 (C~). Presented in p a r t a t t h e P o s t - G r a d u a t e C o u r s e on lV~edical a n d S u r g i c a l P r o b l e m s of Igewborn and Premature Infants, University o f C o l o r a d o S c h o o l of M e d i c i n e , D e n v e r , M a r c h 25, 1954. *An investigation which we have been c o n d u c t i n g f o r f o u r y e a r s , a n d w h i c h is s t i l l being" a c t i v e l y p u r s u e d , is t e s t i n g t h e n e e d f o r t h e r a p y in t h e g r o u p f r o m o n e to t w o y e a r s . Our' i n f o r m a t i o n t h u s f a r w o u l d t e n d to s h o w t h a t t h e r a ! o y in t h i s a g e g r o u p is j u s t a s i m p o r t a n t a s in t h e g r o u p u n d e r o n e y e a r .

~/[.D., AND

sents a changing relationship between man and the tubercle bacillus unrelated to the many treatments that have been tried. 2 A realization of the existence of this dynamic rather than static relationship is important in attempting to evaluate "cures" for tuberculosis; and it should point up the inadequacy of studies of the efficiency of antituberculosis drugs which are based on comparison of present-day treated cases with similar untreated cases of ten years ago. There is good evidence that primary tuberculosis in infants is more likely to go on to become so-called progressive pri m ary disease than in older children. Hettich 3 points out that the risk of progressive manifestations developing decreases the later the child comes into contact with tuberculosis. Among 1,117 infants and young children with tuberculosis, about 25 per cent showed manifestations of progressive primary disease. Of these, 60 per cent were in the age group under 3 years. He concludes that there is a good chance of progressive tuberculosis developing in one-third of infants under one year of age with primary tuberculosis. These figures were obtained in the period prior to antimicrobial therapy. In addition, in observations of 622 children with manifest primary tuberculosis followed at the Children's Chest Clinic, Bellevue Hospital, New 398

M E Y E R E T AL. :

PRIMARY TUBERCULOSIS IN INFANCY

York City, during the pretreatment period, Edith Lincoln 4 has reported that 55 per cent of children under 6 months of age died, 28 per cent of those ] to 2 years of age died, and 15 per cent of those 4 to 9 years of age died. Finally, when progressive primary tuberculosis does occur in infancy, it tends to take the form of the two most malignant types, namely, miliary tuberculosis and tuberculous meningitis. The chief aim, then, of our approach to the problem of active primary tuberculosis in the infant is the prevention of the malignant forms of progressive pr i m ar y tuberculosis. There can be little argument with the categorical statement that any infant with a positive tuberculin test, whether sick or well, with or without an abnormal roentgenogram of the chest, must be considered to have active tuberculosis with the potentiality for progression. Various studies, especially those by tIolm, 5 in 1947, and Wa!lgren, 6 in 1939, have indicated that primary disease may begin to regress three to five months after the onset, but that f u r t h e r evidence of healing and calcification of lesions may occur up to two to three years from the onset. I f this be true, then it must be obvious that any child less than 12 months of age with a positive tuberculin test may justifiably be considered to have active or " u n h e a l e d " tuberculosis. ttaving agreed to this, namely, that all infants with positive tuberculin tests have active disease, it behooves us to find those who have positive tuberculin tests. This is by way of making a very special plea for the routine use of the tuberculin test during the first years of life. It

399

is distressing to see how many doctors caring for children fail to use this simple, accurate test routinely, even though they use many other routines in their well-child care. We should like to suggest that the test be done during the first year of life, at the end of the second, and every three years thereafter. From a practical point of view, we have found that old tuberculin is most satisfactory. For routine testing a dilution of 1:1,000 is employed. Lederle's concentrated old tuberculin is used and diluted as indicated with a phosphate saline buffer. The buffer is prepared as follows: Use 14.2 Gm. NaHP04 and 80.0 Gm. NaC1. Make up to one liter with distilled water. Adjust ph to 6.5. Autoclave for ten minutes. This buffer solution is then diluted ten times with sterile distilled water. After the old tuberculin concentrate is diluted with the phosphate sMine buffer, it may be used for three to six months if stored in a cool place. If laboratory facilities are not available to the practicing physician for the preparation of old tuberculin, we recommend a 1:1 dilution of second strength PPD for routine intradermal testing. A third less desirable tYpe of tuberculin skin testing is with the Vol]mer patch test. From an entirely different point of view, the doctor finding a child with a positive tuberculin test has a signal responsibility to public health in general. E v e r y child with a positive skin test derives his infection from an open case of tuberculosis--most probably from an a d u l t . By checking the contacts of the child, previously undiscovered cases of open

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tuberculosis can be found. The younger the child, the more easily is this accomplished, as his contacts tend to be fewer. In this regard, stress should be placed on the elderly person, particularly grandparents, as a source of infectionJ These individuals commonly control tuberculous disease well, and no one may suspect that grandfather's "cigarette c o u g h " is in reality tuberculosis, and that every time he handles his precious grandchild, he sprays her with tubercle bacilli. The problem then, after having found the infant with a positive tuberculin, and after having separated him from his contact, is the handling of this infant. F or the purpose of clarifying the nature of this problem, let us divide all infants into four groups as follows : (1) Infants with no known exposure to tuberculosis. (2) Infants with negative tuberculin tests and a known contact. (3) Infants with positive tuberculin test, but with no x-ray evidence of tuberculosis. (4) Infants with positive tuberculin tests, and x-ray evidence of tuberculosis. INFANTS WITH

NO KNOWN

EXPOSURE

TO TUBERCULOSIS From this group, we have already discussed the necessity for routine tuberculin testing in order to pick up those unknowingly exposed. INFANTS

WITH

NEGATIVE TUBERCULIN

TESTS AND A KNOWN

CONTACT

These children should, immediately be separated contact. We feel, as does can Trudeau Society s and

of course, from their the Amerithe United

OF PEDIATRICS

States Public Health Service, U that this group is entitled to vaccination with BCG. We are particularly impressed by the statement of Wallgren 1~ that no miliary tuberculosis or tuberculous meningitis has been observed in the Scandinavian countries in a child properly vaccinated with BCG. In the next two groups with active tuberculosis, we feel that specific antimierobial t herapy is indicated. The practical problem is the formulation of a plan of management of the infant with active primary pulmonary tuberculosis. This proposed plan represents our carefully considered conclusions which are derived from our experience with tuberculosis in children. In a field that is rapidly changing, our opinions may also change rapidly. INFANTS WITH

POSITIVE TUBERCULIN

AND WITHOUT

X-RAY EVIDENCE

OF T U B E R C U L O S I S

These infants have active tuberculosis even though their pulmonary lesions are not visible roentgenologically. However, in general, their disease is not as extensive as in the group with positive roentgen findings. A course of isonicotinic acid hydrazide (INH) is prescribed for all these infants. Streptomycin is not given to this group of patients. These children are all apparently well and many parents would object to the biweekly administration of streptomycin by injection. In ~addition, it would be psychologically traumatizing to both parents and child to. undergo this treatment, a result obviated by the administration of oral medication. There is evidence presented by Weintraub 11 and StewarW of a lower

M E Y E R E T AL. :

PRIMARY

incidence of postprimary tuberculosis in the child with negative x-ray findings in comparison to those with positive x-ray findings. Also, at Bellevue Hospital, New York, Edith Lincoln4 noted a mortality of 10 per cent in the group with tuberculosis under 2 years of age without positive roentgen findings; and a mortality of 32 per cent in the same age group with positive roentgen findings. These observations were made before the advent of streptomycin. On the basis of this evidence, we have decided to give only INH to this group of infants. The dosage of INH given is 8 rag. per kilogram per day by mouth for six months, then the dosage is reduced to 4 rag. per kilogram per day. The reduced dosage is continued for a minimum of three months. In a small group of infants treated thus far, according to this protocol, one infant has converted his tubereulin skin test to n e g a t i v e after six months of therapy. Although, as a result of this treatment, the infant may lose all hypersensitivity to tuberculin, he probably retains much of his acquired ability to manifest immunity to exogenous reinfection as has been demonstrated in animals by Corper and associates, a3 There have been some authorities who felt that the infant with primary tuberculosis should not be treated for fear of developing drug-resistant organisms. Trepidation was expressed that serious complications due to drugzresistant tubercle bacilli might subsequently develop. This argument, it seems to us, is fallacious in view of the following considerations: (1) It is our opinion, derived from extensive clinical experience, 1~ that

TUBERCULOSIS IN INFANCY

401

nearly all INH-resistant mutants of tubercle bacilli are attenusted in virulence for' human beings as well as for certain experimental animals. 15-17 Therefore, microbial resistance to INH has clinical implications uniquely different from microbial resistance to other chemotherapeutic agents. (2) If chemotherapy is going to fail when applied early during the course of tuberculous infeetion, or, indeed, of any infection, then treatment is bound to fail later when the multiplying" population of tubercle baeilli is, of necessity, much larger. INFANTS WITtI

POSITIVE TUBERCULIN

AND X - R A Y E V I D E N C E OF T U B E R C U L O S I S

This group of patients requires vigorous therapy in order to prevent the serious complications, miliary tuberculosis and tuberculous meningitis, which occur in highest frequency in this group. It is our opinion that INH is the most important drug for the long-term therapy of tuberculosis; however, when it is important to sterilize as many tubercle bacilli as possible early in treatment, another drug which is synergistic with INH should be simultaneously administered. Therefore, we use streptomycin sulfate for short-term early therapy in addition to INH. INH is given 8 rag. per kilogram per day for six months, then reduced to 4 rag. per kilogram per day for a minimum of three months. Streptomycin sulfate is given according to the dosage schedule in Table I (arrived at by corrected accepted adult dosage on a surface area basis) for a period of one month. It should be stressed that streptomycin sulfate and not combinations of streptomycin sulfate and dihydrostreptomyein has been used. Observations by D r . Nicolas Espinosa .8

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THE JOURNAL OF PEDIATRICS

at National Jewish Hospital indicate that hearing loss following the use of combinations of streptomycin and dihydrostreptomycin has been as great as when dihydrostreptomycin alone was used. TABLE I

KILOGRAI~ WEmHT 2 3 4

DOSAGEOl~ STREPTOMYS1N SULFATEI. M. EVERYTtlREE DAYS (G~.) 0.100 0.150 0.200

10 15 20

0.5.00

40 50 60 I 68

1.00O

0.750

1.500

SUMMARY

1. The management of the infant under one year with primary pulmonary tuberculosis has received inadequate attention in the past. 2. The malignant forms of progressive primary tuberculosis, i.e., miliary tuberculosis and tuberculous meningitis, occur with greatest frequency during infancy, and should be prevented whenever possible. 3. All infants and children should routinely be tested with tuberculin in order to detect early the presence of primary tuberculosis. 4. BCG should be given to those likely to be exposed to tuberculosis. 5. Infants with a positive tuberculin and negative x-ray findings should receive a course of INH. 6. Infants with a positive tuberculin and positive x-ray findings should receive INH and streptomycin sulfate. CONCLUSION

We feel that this simple plan of management of the infant in relation

to tuberculosis may be generally applied. REFERENCES 1. Rich, A. 1 ~ . : The P a t h o g e n e s i s of Tuberculosis, ed. 2, Springfield, Ill., 1951, Charles C Thomas, Publisher, p. 220. 2. Dubos, R., and Dubos, J.: The W h i t e Plague, Boston, 1953j Little, B r o w n and Co., ch. X l I . 3. I t e t t i e h , I.: On Frequency and Localization in Tuberculous Disease of the Secondary Stage in I n f a n c y a n d Children, Ztschr. f. Tuberk. 82: 126, 1939. 4. Lincoln, E. M.: Course and Prognosis of Tuberculosis in Children~ Am. J. M e d / 9 : 623, 1950. 5. Holm, S.: Om den friske tuberkulose infektion~ dens, klinik, prognose og behandling, Kbpenhamm, 1947. 6. Wallgren, A., Tuberculosis in Children, N e l s o n ' s New Loose L e a f Medicine, vo]. I, New York, 1939. 7. Myers, J. A.: Tuberculosis Among Children and Adults, ed. 3, Springfield, IlL, 1951, Charles C Thomas~ Publisher, p. 67. 8. A m e r i c a n Trudeau Society, S t a t e m e n t on BCG, Am. gev. Tuberc. 60: 681, 1949. 9. Anderson, R. J.: Licensure of BCG Vaccine, Pub. Health Rep. 65: 963, 1950. 10. Wal]gren, A . J . : BCG Vaccination, in A d v a n c e s in Pediatrics, edited b y S. Z. Levine, Chicago, ]952, Year Book Publisher, Inc., vol. 5, p. 249. 11. W e i n t r a u b , W. L.:- Tuberculin Positive Children Observed for Various Periods of Time up to Five Years, Am. Rev. Tuberc. 33: 247, 1936. 12. Stewart, C. A.: Does a P r i m a r y Infection Afford Adequate Protection A g a i n s t Consumption? J. A. M. A. 100: 1077, 1933. 13. Corper, I s J., Cohn, M. L., and Damerow, A. P.: Relations Between Specific I m m u n i t y , Allergy, and Anaphylaxis in Tuberculosis, Am. J. C1in. Path. i0: 361, 1940. 14. Oestreicher, R., Dressier, S. I-L, Russell, W. F., Jr., Grow, J. B., and Middlebrook, G.: Observations on the Pathogenicity of Isoniazid-resistant M u t a n t s of Tubercle Bacilli for Tuberculous Patients, Am. Rev. Tuberc. & Fulm. Dis. 7 1 : 1 9 5 5 (in press). 15. Middlebrook, G., and Cohn, M. L.: Some Observations on the P a t h o g e n i c i t y of Isoniazid-resistant V a r i a n t s of Tubercle Bacilli, Science 118: 297, 1953. ]6. Barry, V. C., Conalty, M. D , and Gaffhey, E.: Isoaiazid-resistant S t r a i n s of Mycobacterium Tuberculosls~ L a n c e t 1: 979, 1953. 17. Mitchison, D. A.: Tubercle Bacilli R e s i s t a n t to Isoniazid. Virulence and Response to T r e a t m e n t in Guinea-Pigs, Brit. M. J. 1: 128, 1954. 18. Espinosa, N.: Personal communication.