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Generalized BCG infection
COMMENTS CURRENT
ON LITERATURE
Generalized BCG infection lymphadenitis followed intradermal BCG vaccination, especially in young childrenY While, as a rule, BCG infection does not become generalized, there is evidence that following BCG vaccination a hematogenous dissemination of the organism does occur with the formation of small circumscribed loci in many organs2 In a few recorded instances this dissemination has resulted in a disease state. According to Wallgren's 4 survey in 1961, eight fatal cases had been recorded to that date. In 1963 Gardborg 5 and his associates described in detail the course of an infant who received BCG vaccine intraeutaneously at the age of 6 weeks, and who died at the age of 7 months of generalized BCG infection. At the time of this child's birth the father was in a sanatorium under treatment for pulmonary tuberculosis, having been admitted to the sanatorium because of an exudative outbreak of an old previously inactive process. The father's response to drug therapy was prompt and sustained, with satisfactory clinical results. The first child of the family reported by Gardborg was a boy born in 1955 who died at 5 months of age following an eight weeks' hospitalization. Necropsy study revealed enteritis, bilateral otitis media, and bronchopneumonia. H e had not been vaccinated with BCG and nothing is known as to his tuberculin reaction. The family's second child, a girl born in 1956, died at 5 89 months
S e v E R A L means of vaccination against tuberculosis have been employed. These methods appear to give a partial immunity of variable duration. The best known and most widely employed procedure involves the use of BCG vaccine containing the bacillus of Calmette and Gu&in, believed to be a mutant strain of the bovine tubercle bacillus which emerged during long cultivation on bile-glycero-potato medium. The BCG strain "resembles the human type of tubercle bacillus in its morphology, cultural appearance, eugonic growth and areophilic nature, but the bovine type, from which it is derived, in its biochemical properties and drug sensitivity pattern." It is "resistant to pyrazinamide, sensitive to thiosemicarbazone, arylsulphatase positive, and niacin negative. ''1 The strain has little virulence for guinea pigs but sensitizes them strongly to tuberculin. This organism, which is essentially avirulent, is contained in BCG vaccine as a living culture. For a time the bacilli multiply in the body; commonly they spread to regional lymph nodes where they remain for several months. The lesions produced by the BCG strain are those characteristic of the disease tuberculosis; they may lead to caseation or even to calcification. In general, however, BCG infection differs from tuberculosis in the rapid retrogression and complete disappearance of the local lesions. A few instances have been reported in which suppurative 3ll
3 12
Comments
on current literature
of age after repeated hospitalization. This infant had suffered intermittently from diarrhea and vomiting, episodes of coughing, dyspnea, and cyanosis. During the final hospitalization she showed signs of heart failure. The clinical diagnosis was congenital heart disease with myocarditis. No autopsy was performed. No information was available concerning BCG vaccination or tuberculin status. The third child, a girl born in 1959, is in good health. She was vaccinated with BCG in June, 1960; the course following this vaccination was uneventful and the child became Pirquet positive. The patient described in the current report was the fourth child, a girl born in September, 1960. Following a Pirquet tuberculin test which was negative, this infant received BCG vaccine intracutaneously at 6 weeks of age. From the first few days of life the child had not thrived and suffered from recurrent diarrhea and oral moniliasis. At 14 weeks of age, the Pirquet reaction was still negative, but no further vaccination was attempted. During the early months of life this infant had been hospitalized in local hospitals, and was referred for further study at 6 ~ months of age to the Pediatric Department, Rikshospitalet, Oslo. Despite intensive therapy, the course was unfavorable from the day of admission. Autopsy studies revealed disseminated tuberculosis. There was marked caseous necrosis with m a n y acid-fast organisms in the affected areas. A tumorlike mass in front of the pancreas consisted of greatly enlarged-lymph nodes with necrotic areas limited by granulation tissue. Special staining methods revealed many acid-fast rods in the areas of necrosis and in the granulation tissue. Similar pathologic changes with large numbers of acid-fast organisms were observed in the spleen, the renal capsule, in both adrenal glands, and in the lungs and liver. Changes in the brain and the meninges were nonspecific. On bacteriologic study, the acidfast organisms appeared to be of the BCG strain. Since two of the patient's siblings had shown early signs of reduced resistance, and both had died from generalized bacterial infection, impaired resistance in this patient
August 1964
was considered to be an important factor in the dissemination of BCG organisms. Two more recent reports deal with hypogammaglobulinemia and agammaglobulinemia as a possible basis for generalized BCG infection. The first of these, from the Children's Hospital in Liverpool, 6 concerns a child with congenital hypogammaglobulinemia who died at 9 months of age. This male infant, the first child of healthy parents, was born in a section of .Liverpool in which tuberculosis is relatively prevalent. All babies born in this district of the city are vaccinated with BCG unless parental consent is refused. This patient was vaccinated on the fourth day of life. Six months later he was referred to the Children's Hospital because of a swelling in the left axilla. At this time, a lesion at the site of the BCG vaccination over the left deltoid, which had developed at 6 weeks of age, was still discharging. The infant was admitted to the hospital for evaluation and for incision of the axillary abscess, from which thick green pus was removed. No organisms were seen on direct smear, and none could be cultured by routine methods. One month later neither the original BCG vaccination lesion nor the axillary lesion had healed. For the next three months the clinical course was stormy. The local lesions did not heal, and in spite of treatment with streptomycin, p-aminosalicylic acid, isoniazid, and g a m m a globulin, the child's condition deteriorated. Paper-strip eleetrophoresis showed increased alpha2-globulin, and very low g a m m a globulin level. Necropsy studies revealed widespread BCG infection with acid-fast bacilli present in many organs. In a recent issue of A e t a p a e d i a t r i c a 7 a family of three children is described: a son who died of generalized BCG infection at the age of 8 months, a daughter 6 years of age, living and well, and a second son who died at 5 months of age of septicemia associated with congenital agammaglobulinemia. The first-born son was vaccinated with BCG on the left thigh by intradermal injection at 5 days of age. By 6 months of age this infant had developed lymphadenitis of the left groin. Recurrent fever and a cough in the
Volume 65
Number 2
early months of life were treated by penicillin; defervescence followed treatment, but the cough persisted. At 8 months of age the child was admitted in very poor condition to the Pediatrics Department of the University of Uppsala. He was dyspneic and cyanotic, with an area of necrosis 20 mm. in diameter at the site of the BCG vaccination and enlarged lymph nodes in the left groin. X-ray examination of the chest disclosed a large opacity in the upper lobe of the left lung, and later also in the right lung. The white blood cell count was 6,900, with 23.5 per cent lymphocytes, but no plasma cells. The Mantoux test was negative. Despite intensive treatment, the child died twelve days after admission to the hospital. Necropsy studies revealed generalized tuberculosis with acid-fast bacilli in many organs. On detailed bacteriologic investigation, the acid-fast strains isolated were indistinguishable from BCG. The second child of this family, a girl, was healthy, not unduly susceptible to infection, and was vaccinated with BCG without complication. She was 6 years of age at the time of the current report. The third child of the family, a boy, did not thrive in early life and was extremely susceptible to bacterial infection. While this infant had a negative Mantoux test, he was not vaccinated with BCG, in view of his brother's death from disseminated BCG infection. He was treated for recurrent infection by various antibiotics including penicillin, tetracycline, and Chloromycetin, as advisable, and subsequently by gamma globulin. Detailed electrophorectic studies showed an abnormal serum protein pattern in the boy and in his father. Special studies utilizing appropriate methods of immunoelectrophoresis revealed that the 7-S g a m m a globulin level was very low in this child. No beta2~ globulin, and only traces of beta2A globulin could be demonstrated. The child died at 5 months of age. The findings on postmortem exmnination were described as those associated with congenital agammaglobulinemia. The thymus was markedly hypoplastic, showing pronounced lymphoid hypoplasia and only small
Comments on current literature
3 13
scattered groups of lymphocytes. On the other hand, hyperplastic reticuloendothelial cells were abundant. Lymph nodes and other lymphoid tissues were greatly reduced, with marked changes in the nodes present, the lymph follicles being small and atrophic, while the reticuloendothelial component was hyperplastic. T h e spleen was enlarged with hyperplastic reticuloendothelium, but with no areas of necrosis. The liver was enlarged; large yellowish-white foci, which were apparent on gross examination, consisted microscopically of confluent areas of necrosis surrounded by a few lymphocytes and granulocytes. In and around these necrotic areas were large numbers of gram-negative rodshaped bacteria. There was no evidence of inclusion body formation. The adrenal glands were normal in size; the cortex contained many small areas of necrosis with no inflammatory cellular reaction. Gram-negative rods were present in these necrotic loci. In the brain, the basal ganglia showed scattered patches of perivascular infiltration with no necrosis. In the lungs, small areas of atelectasis and hemorrhage were noted, but there were no signs of pneumonia. Cultures of blood, and of tissue from the lung, liver, spleen, kidney, and gut yielded Pseudomonas aeruginosa in all samples. From the gut Bacillus coli also was isolated. No acid-fast organisms were seen in the tissues, and none could be cultured. A strain of adenovirus type 2 was isolated from the liver, the brain, and the myocardium. The protective value of BCG vaccination has been demonstrated beyond question: s, 4, 8, 9 Considering the large number of persons receiving BCG vaccine during the past 10 to 15 years, serious complications appear to be rare. Nevertheless, as these recent reports emphasize, the potential dangers of a vaccine of viable organisms, such as the BCG vaccine, or the living vole vaccine derived from a murine strain of tubercle bacillus, must be given due consideration. BCG vaccine is contraindicated in patients with positive tuberculin reactions. BCG vaccination should be undertaken with caution in cases of severe allergy, or of debilitation from
3 14
C o m m e n t s on current literature
metabolic disturbance or recurrent infection. O t h e r contraindications listed in the Report of the Committee on the Control of Infectious Diseases, A m e r i c a n A c a d e m y of Pediatrics, include "hypogammaglobulinemia, agammaglobulinemia, skin infections, fresh smallpox vaccination a n d burns. ''1~ RUSSELL J. BLATTNER~ M.D. REFERENCES 1. Marks, J.: Disseminated BCG infection (Letter to the Editor), Brit. M. J. 1: 1737, 1963. Marks, J., and Trollope, D. R.: A study of the "anonymous" mycohacteria: I. Introduction; colonial characteristics and morphology; growth rates; biochemical tests, Tubercle 41: 51, 1960; II. Drug sensitivity; pathogenicity; hypersensitivity, Tubercle 41: 127, 1960; III. Problems of classification and diagnosis; practical recommendations, Tubercle 41z 133, 1960. 2. Guld, J., Magnus, K., Tolderlund, K., Biering-Sorensen, K., and Edwards, P. Q.: Suppurative lymphadenitis following intradermal BCG vaccination of the newborn, Brit. M. J. 2: 1048, 1955. 3. Gormsen, HarM& On the occurrence of epitheloid cell granulomas in the organs of BCGvaccinated human beings, Acta path. et mierobiol, scandinav, supp. 111: 117, 1956. Strom, Lars: Vaccination against tuberculosis: Session 2, Proceedings of the Symposium on Tuberculosis in Infancy and Childhood, Am. Rev. Tuberc., supp. 74: 28, 1955.
August 1964
4. Wallgren, A. J.: Einige Probleme der Calmetteschen Impfung, Deutsche med. Wchnschr. 86: 105, 1961. 5. Gardborg, Odd, Iversen, O. I-I., Torheim, B. J., and Hesselberg, Ivar: Generalized BCG infection with fatal course in an infant, Acta paediatriea 52: 293, 1963. 6. Bouton, J., Mainwaring, D., and Smithells, R. W.: B. C. G. dissemination in congenital hypogammaglobulinaemia, Brit. M. J. 1: 1512, 1963. 7. Bonnevier, J. O., Killander, Johan, Olding, Lars, and Vahlquist, Bo: Congenital agammaglobulinaemia in the brother of a boy who died of generalized BCG infection, Acta paediat. 53: 55, 1964. 8. Wallgren, A. J.: BCG vaccination: Past, present, and future, Am. Rev. Tuberc. 76" 715, 1957. Miller, F. J. W., Seal, R. M. E., and Taylor, M. D.: Tuberculosis in children: Evolution, control, and treatment, Boston, 1963, Little, Brown and Co. 9. Third Report of the Medical Research Council Tuberculosis Vaccines Clinical Trials Committee: B. C. G. and vole bacillus vaccines in the prevention of tuberculosis in adolescence and early adult life, Brit. M. J. 1: 973, 1963. Hart, P. D'Arcy, Mitchell, D. N., and Sutherland, Ian: Associations between Kveim test results, previous B. C. G. vaccination, and tuberculin sensitivity in healthy young adults, Brit, M. J. 1: 795, 1964. 10. American Academy of Pediatrics: Report of the Committee on the Control of Infectious Diseases: Lewis L. Corriell, Chairman: Tuberculosis, ed. 14, Evanston, Ill., p. 25.
ON LITERATURE
Generalized BCG infection lymphadenitis followed intradermal BCG vaccination, especially in young childrenY While, as a rule, BCG infection does not become generalized, there is evidence that following BCG vaccination a hematogenous dissemination of the organism does occur with the formation of small circumscribed loci in many organs2 In a few recorded instances this dissemination has resulted in a disease state. According to Wallgren's 4 survey in 1961, eight fatal cases had been recorded to that date. In 1963 Gardborg 5 and his associates described in detail the course of an infant who received BCG vaccine intraeutaneously at the age of 6 weeks, and who died at the age of 7 months of generalized BCG infection. At the time of this child's birth the father was in a sanatorium under treatment for pulmonary tuberculosis, having been admitted to the sanatorium because of an exudative outbreak of an old previously inactive process. The father's response to drug therapy was prompt and sustained, with satisfactory clinical results. The first child of the family reported by Gardborg was a boy born in 1955 who died at 5 months of age following an eight weeks' hospitalization. Necropsy study revealed enteritis, bilateral otitis media, and bronchopneumonia. H e had not been vaccinated with BCG and nothing is known as to his tuberculin reaction. The family's second child, a girl born in 1956, died at 5 89 months
S e v E R A L means of vaccination against tuberculosis have been employed. These methods appear to give a partial immunity of variable duration. The best known and most widely employed procedure involves the use of BCG vaccine containing the bacillus of Calmette and Gu&in, believed to be a mutant strain of the bovine tubercle bacillus which emerged during long cultivation on bile-glycero-potato medium. The BCG strain "resembles the human type of tubercle bacillus in its morphology, cultural appearance, eugonic growth and areophilic nature, but the bovine type, from which it is derived, in its biochemical properties and drug sensitivity pattern." It is "resistant to pyrazinamide, sensitive to thiosemicarbazone, arylsulphatase positive, and niacin negative. ''1 The strain has little virulence for guinea pigs but sensitizes them strongly to tuberculin. This organism, which is essentially avirulent, is contained in BCG vaccine as a living culture. For a time the bacilli multiply in the body; commonly they spread to regional lymph nodes where they remain for several months. The lesions produced by the BCG strain are those characteristic of the disease tuberculosis; they may lead to caseation or even to calcification. In general, however, BCG infection differs from tuberculosis in the rapid retrogression and complete disappearance of the local lesions. A few instances have been reported in which suppurative 3ll
3 12
Comments
on current literature
of age after repeated hospitalization. This infant had suffered intermittently from diarrhea and vomiting, episodes of coughing, dyspnea, and cyanosis. During the final hospitalization she showed signs of heart failure. The clinical diagnosis was congenital heart disease with myocarditis. No autopsy was performed. No information was available concerning BCG vaccination or tuberculin status. The third child, a girl born in 1959, is in good health. She was vaccinated with BCG in June, 1960; the course following this vaccination was uneventful and the child became Pirquet positive. The patient described in the current report was the fourth child, a girl born in September, 1960. Following a Pirquet tuberculin test which was negative, this infant received BCG vaccine intracutaneously at 6 weeks of age. From the first few days of life the child had not thrived and suffered from recurrent diarrhea and oral moniliasis. At 14 weeks of age, the Pirquet reaction was still negative, but no further vaccination was attempted. During the early months of life this infant had been hospitalized in local hospitals, and was referred for further study at 6 ~ months of age to the Pediatric Department, Rikshospitalet, Oslo. Despite intensive therapy, the course was unfavorable from the day of admission. Autopsy studies revealed disseminated tuberculosis. There was marked caseous necrosis with m a n y acid-fast organisms in the affected areas. A tumorlike mass in front of the pancreas consisted of greatly enlarged-lymph nodes with necrotic areas limited by granulation tissue. Special staining methods revealed many acid-fast rods in the areas of necrosis and in the granulation tissue. Similar pathologic changes with large numbers of acid-fast organisms were observed in the spleen, the renal capsule, in both adrenal glands, and in the lungs and liver. Changes in the brain and the meninges were nonspecific. On bacteriologic study, the acidfast organisms appeared to be of the BCG strain. Since two of the patient's siblings had shown early signs of reduced resistance, and both had died from generalized bacterial infection, impaired resistance in this patient
August 1964
was considered to be an important factor in the dissemination of BCG organisms. Two more recent reports deal with hypogammaglobulinemia and agammaglobulinemia as a possible basis for generalized BCG infection. The first of these, from the Children's Hospital in Liverpool, 6 concerns a child with congenital hypogammaglobulinemia who died at 9 months of age. This male infant, the first child of healthy parents, was born in a section of .Liverpool in which tuberculosis is relatively prevalent. All babies born in this district of the city are vaccinated with BCG unless parental consent is refused. This patient was vaccinated on the fourth day of life. Six months later he was referred to the Children's Hospital because of a swelling in the left axilla. At this time, a lesion at the site of the BCG vaccination over the left deltoid, which had developed at 6 weeks of age, was still discharging. The infant was admitted to the hospital for evaluation and for incision of the axillary abscess, from which thick green pus was removed. No organisms were seen on direct smear, and none could be cultured by routine methods. One month later neither the original BCG vaccination lesion nor the axillary lesion had healed. For the next three months the clinical course was stormy. The local lesions did not heal, and in spite of treatment with streptomycin, p-aminosalicylic acid, isoniazid, and g a m m a globulin, the child's condition deteriorated. Paper-strip eleetrophoresis showed increased alpha2-globulin, and very low g a m m a globulin level. Necropsy studies revealed widespread BCG infection with acid-fast bacilli present in many organs. In a recent issue of A e t a p a e d i a t r i c a 7 a family of three children is described: a son who died of generalized BCG infection at the age of 8 months, a daughter 6 years of age, living and well, and a second son who died at 5 months of age of septicemia associated with congenital agammaglobulinemia. The first-born son was vaccinated with BCG on the left thigh by intradermal injection at 5 days of age. By 6 months of age this infant had developed lymphadenitis of the left groin. Recurrent fever and a cough in the
Volume 65
Number 2
early months of life were treated by penicillin; defervescence followed treatment, but the cough persisted. At 8 months of age the child was admitted in very poor condition to the Pediatrics Department of the University of Uppsala. He was dyspneic and cyanotic, with an area of necrosis 20 mm. in diameter at the site of the BCG vaccination and enlarged lymph nodes in the left groin. X-ray examination of the chest disclosed a large opacity in the upper lobe of the left lung, and later also in the right lung. The white blood cell count was 6,900, with 23.5 per cent lymphocytes, but no plasma cells. The Mantoux test was negative. Despite intensive treatment, the child died twelve days after admission to the hospital. Necropsy studies revealed generalized tuberculosis with acid-fast bacilli in many organs. On detailed bacteriologic investigation, the acid-fast strains isolated were indistinguishable from BCG. The second child of this family, a girl, was healthy, not unduly susceptible to infection, and was vaccinated with BCG without complication. She was 6 years of age at the time of the current report. The third child of the family, a boy, did not thrive in early life and was extremely susceptible to bacterial infection. While this infant had a negative Mantoux test, he was not vaccinated with BCG, in view of his brother's death from disseminated BCG infection. He was treated for recurrent infection by various antibiotics including penicillin, tetracycline, and Chloromycetin, as advisable, and subsequently by gamma globulin. Detailed electrophorectic studies showed an abnormal serum protein pattern in the boy and in his father. Special studies utilizing appropriate methods of immunoelectrophoresis revealed that the 7-S g a m m a globulin level was very low in this child. No beta2~ globulin, and only traces of beta2A globulin could be demonstrated. The child died at 5 months of age. The findings on postmortem exmnination were described as those associated with congenital agammaglobulinemia. The thymus was markedly hypoplastic, showing pronounced lymphoid hypoplasia and only small
Comments on current literature
3 13
scattered groups of lymphocytes. On the other hand, hyperplastic reticuloendothelial cells were abundant. Lymph nodes and other lymphoid tissues were greatly reduced, with marked changes in the nodes present, the lymph follicles being small and atrophic, while the reticuloendothelial component was hyperplastic. T h e spleen was enlarged with hyperplastic reticuloendothelium, but with no areas of necrosis. The liver was enlarged; large yellowish-white foci, which were apparent on gross examination, consisted microscopically of confluent areas of necrosis surrounded by a few lymphocytes and granulocytes. In and around these necrotic areas were large numbers of gram-negative rodshaped bacteria. There was no evidence of inclusion body formation. The adrenal glands were normal in size; the cortex contained many small areas of necrosis with no inflammatory cellular reaction. Gram-negative rods were present in these necrotic loci. In the brain, the basal ganglia showed scattered patches of perivascular infiltration with no necrosis. In the lungs, small areas of atelectasis and hemorrhage were noted, but there were no signs of pneumonia. Cultures of blood, and of tissue from the lung, liver, spleen, kidney, and gut yielded Pseudomonas aeruginosa in all samples. From the gut Bacillus coli also was isolated. No acid-fast organisms were seen in the tissues, and none could be cultured. A strain of adenovirus type 2 was isolated from the liver, the brain, and the myocardium. The protective value of BCG vaccination has been demonstrated beyond question: s, 4, 8, 9 Considering the large number of persons receiving BCG vaccine during the past 10 to 15 years, serious complications appear to be rare. Nevertheless, as these recent reports emphasize, the potential dangers of a vaccine of viable organisms, such as the BCG vaccine, or the living vole vaccine derived from a murine strain of tubercle bacillus, must be given due consideration. BCG vaccine is contraindicated in patients with positive tuberculin reactions. BCG vaccination should be undertaken with caution in cases of severe allergy, or of debilitation from
3 14
C o m m e n t s on current literature
metabolic disturbance or recurrent infection. O t h e r contraindications listed in the Report of the Committee on the Control of Infectious Diseases, A m e r i c a n A c a d e m y of Pediatrics, include "hypogammaglobulinemia, agammaglobulinemia, skin infections, fresh smallpox vaccination a n d burns. ''1~ RUSSELL J. BLATTNER~ M.D. REFERENCES 1. Marks, J.: Disseminated BCG infection (Letter to the Editor), Brit. M. J. 1: 1737, 1963. Marks, J., and Trollope, D. R.: A study of the "anonymous" mycohacteria: I. Introduction; colonial characteristics and morphology; growth rates; biochemical tests, Tubercle 41: 51, 1960; II. Drug sensitivity; pathogenicity; hypersensitivity, Tubercle 41: 127, 1960; III. Problems of classification and diagnosis; practical recommendations, Tubercle 41z 133, 1960. 2. Guld, J., Magnus, K., Tolderlund, K., Biering-Sorensen, K., and Edwards, P. Q.: Suppurative lymphadenitis following intradermal BCG vaccination of the newborn, Brit. M. J. 2: 1048, 1955. 3. Gormsen, HarM& On the occurrence of epitheloid cell granulomas in the organs of BCGvaccinated human beings, Acta path. et mierobiol, scandinav, supp. 111: 117, 1956. Strom, Lars: Vaccination against tuberculosis: Session 2, Proceedings of the Symposium on Tuberculosis in Infancy and Childhood, Am. Rev. Tuberc., supp. 74: 28, 1955.
August 1964
4. Wallgren, A. J.: Einige Probleme der Calmetteschen Impfung, Deutsche med. Wchnschr. 86: 105, 1961. 5. Gardborg, Odd, Iversen, O. I-I., Torheim, B. J., and Hesselberg, Ivar: Generalized BCG infection with fatal course in an infant, Acta paediatriea 52: 293, 1963. 6. Bouton, J., Mainwaring, D., and Smithells, R. W.: B. C. G. dissemination in congenital hypogammaglobulinaemia, Brit. M. J. 1: 1512, 1963. 7. Bonnevier, J. O., Killander, Johan, Olding, Lars, and Vahlquist, Bo: Congenital agammaglobulinaemia in the brother of a boy who died of generalized BCG infection, Acta paediat. 53: 55, 1964. 8. Wallgren, A. J.: BCG vaccination: Past, present, and future, Am. Rev. Tuberc. 76" 715, 1957. Miller, F. J. W., Seal, R. M. E., and Taylor, M. D.: Tuberculosis in children: Evolution, control, and treatment, Boston, 1963, Little, Brown and Co. 9. Third Report of the Medical Research Council Tuberculosis Vaccines Clinical Trials Committee: B. C. G. and vole bacillus vaccines in the prevention of tuberculosis in adolescence and early adult life, Brit. M. J. 1: 973, 1963. Hart, P. D'Arcy, Mitchell, D. N., and Sutherland, Ian: Associations between Kveim test results, previous B. C. G. vaccination, and tuberculin sensitivity in healthy young adults, Brit, M. J. 1: 795, 1964. 10. American Academy of Pediatrics: Report of the Committee on the Control of Infectious Diseases: Lewis L. Corriell, Chairman: Tuberculosis, ed. 14, Evanston, Ill., p. 25.