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Immunization Dialogue Indian Pediatrics 1999;36: 941-944 |
BCG Vaccination: Some Practical Dilemmas |
TB has been classified as one of the six vaccine preventable diseases by WHO and BCG vaccination has been made a part of the National Immunization Program in India and abroad. BCG induced protection is essentially elicited through the generation of appropriate cell mediated immunity (CMI). Eight controlled trials of BCG vaccination conducted all over the world have shown the protective efficacy of BCG to be 0-80%(4). Particularly, BCG vaccination has been shown to reduce the incidence of disseminated TB and tubercular meningitis (TBM) in vaccinated children.The protective efficacy of the vaccine against these two forms of tuberculosis is 70-80%(5,6). The British Medical Research Council trial in 1959 too showed a 100% protection dependent on the roles played by TH1 and TH2 cells. A TH1 dominant response leads to CMI and a TH2 dominant response results in efficient humoral immunity. TH1 cells operate through the production of IL-2 and IFN-g cytokines while TH2 cells accomplish their function by secreting, among others, IL-4, IL-6 and IL-10. These two types of T cells can obfuscate the optimal response of each other through their cytokines. While the mechanistic details of the suppression/ enhancement of cellular or humoral response through the cytokines of TH1 or TH2 are being unravelled, the primary question as to why some individuals are strong TH1 responders while others are strong TH2 responders, for the same T-dependent antigen, remains unresolved(7). Perhaps, the disparate results of BCG vaccine trials may be amenable to scrutiny through analysis of the relative dominance of the TH1 or TH2 response. The success of any immunization program is judged by the development of immunity against the disease for which vaccination has been done, that is reflected by reduction in the incidence and eventual control/eradication of the disease from the community. It is important to note that vaccination is a process of administration of an antigen into the body, whereas, immunization refers to the development of active immunity, be it cell mediated, humoral or both against the antigen administered in the body which in turn prevents the development of disease by the same organism. It is, therefore, not the BCG vaccination coverage of the child population which is important, but the development of immunity against acquiring tuberculosis by the population in general and by children in particular. Recently it has been suggested that absence of local lesion and scar formation at the site of inoculation may be indicative of unsuccessful BCG vaccination in an individual(8) and that tuberculin skin test (PPD) can be taken as a test for BCG vaccine uptake(9). We do not agree with both these inferences. Neither absence of BCG scar formation nor negative PPD re- action after BCG vaccination is indicative of poor BCG uptake(10-12). In fact Surekha Rani et al.(12) have found that BCG scar was absent in significant number of babies (p <0.05) vaccinated within 48 hours of birth. In the same study, the leukocyte migration inhibition (LMI) test was positive in 88.2% of babies each with or without scar indicating adequate CMI against BCG. Therefore, there is no need to repeat BCG inoculation in babies who do not develop BCG scar as advocated in the guidelines of IAP 1996(6). Similarly, there is wide variation in the tuberculin conversion in BCG vaccinated infants as reported by various authors. In a study(13) the tuberculin conversion done at 8 weeks after BCG vaccination ranged from 83%-93% in pretern and term infants immunized at birth or at 40 weeks post conceptional age. Kebede reported a tuberculin conversion rate of 59% 12 weeks after BCG vaccination in infants 6 to 24 months of age(14). Vidal et al.(15) reported that of the newborns vaccinated at birth, 12.2% were tuberculin negative at 3 months while the same group showed a significant increase in tuberculin positivity at 1 year. Therefore a single negative value of Mantoux test taken at 3 months after BCG vaccination cannot be relied upon and a repeat Mantoux testing is required at one year. But we cannot afford to wait for a year to see BCG uptake because if the child does not possess adequate BCG immunity after vaccination he/she will be vulnerable to acquire the disease during this period. Further let us take the case of Mantoux test measurement per se. The test is read by measuring the size of induration after 48-72 hours commonly by palpation method or more precisely by ballpoint pen technique which is not routinely done in our country. In a recent study(16) it was found in 5% of cases that intraobserver variation in the two measurements of Mantoux test reading was from 2.7 mm less to 3mm more and interobserver variation was 3.4 mm less to 3.7 mm more from the first observer. Again the area of imprecision was 38% less broad for the ballpoint technique than the palpation method. This could make a positive test result negative and vice versa. Hence, absence of scar or negative Mantoux test cannot be taken as the sole criterion for presence or absence of BCG uptake. The question of BCG uptake is more important in case of low birth weight babies because it is not known whether the vaccine is as immunogenic or protective in infants who suffer from prematurity and/IUGR as compared to appropriate for gestational age babies. In India approximately 30-40% babies are low birth weight (LBW) and 7-22% are preterm(17). It is important to know whether the practice of BCG vaccination immediately after birth holds true for low birth weight infants as well. In India, it is recommended that BCG should be given to all newborns within 2 weeks of birth, as part of the National Immunization Program along with zero dose of OPV. Then at 6 weeks of age, i.e., after a minimum gap of 4 weeks, the 1st dose of DPT/OPV is given with the second and third doses being given subsequently at 4 weeks interval. In LBW babies the BCG vaccination may be delayed especially in babies weighing <1800g or those needing specialised care. If BCG/OPV zero dose is delayed by 3-4 weeks further vaccination gets progressively delayed thus keeping the baby at risk to acquire all these dangerous infections for a longer period. If BCG is given at 6 weeks, to minimize hospital visits the baby remains vulnerable to acquire tuberculosis for longer period as 8-12 weeks are normally required for development of immunity. There are studies which have shown that when BCG is given at birth to low birth weight babies, they show a poor Mantoux conversion and defective LMI response as compared to AGA babies(18, 19). Therefore we would like to know the evidence based scientific reasons for or against the following situations: 1. What is the minimum gestational age at which BCG can be given within 2 weeks of birth? 2. At what minimum birth weight BCG vaccination should be done within 2 weeks of birth? 3. At what chronological age, a £1200 g baby can be given BCG vaccination? 4. At what chronological age, a 26-32 weeks baby can be given BCG vaccination? Sarvpreet Kaur, References 1. Seth V, Kabra SK, Seth R. Epidemiology - I. Special reference to children. In: Essentials of Tuberculosis in Children. Ed. Seth V. New Delhi, Jaypee Brothers, 1997; pp 5-8. 2. Tuberculosis. Wkly Epi Record. 1997; 72: 117-124. 3. National Tuberculosis Control Programme, National Health Programme. Annual Report, Ministry of Health and Family welfare, New Delhi, 1997-98; pp 150-153. 4. Ten Dam BG, Toman K, Hitze KL, Guld J. Present knowledge of immunization against tuberculosis. Bull WHO 1976; 54: 255-262. 5. Udani PM. BCG vaccination in India and tuberculosis in children, newer facets. Indian J Pediatr 1994; 61: 451-462. 6. EPI vaccines - BCG. In: IAP Guidebook on Immunization. Mumbai, Indian Academy of Pediatrics 1996; pp 18-19. 7. Roitt MI. Type IV - Cell mediated hypersensitivity. In: Roitts Essential Immunology. Ed. Roitt MI. Oxford, Blackwell Science Ltd. 1997; pp 346-348. 8. Chaparas SD. Immuniologically based diagnostic tests with tuberculin and other mycobacterial antigens. In: Mycobacteria: A Source Book. Ed. Kubica GP. New York, Marcel Dekker Inc, 1983; pp 195-210. 9. John TJ. Tests for vaccine efficacy. Indian Pediatr 1988; 35: 284-285. 10. Rajaje S, Narayanan PR. Immune response to BCG vaccination in children. J Trop Pediatr 1985; 35: 185-188. 11. Vijayalakshmi V, Devi PS, Murthy KJR, Rao DV, Jain SN. Cell mediated immune response in BCG vaccinated children. Indian Pediatr 1993; 30: 899-903. 12. Surekha RH, Vijaylakshmi V, Kumar S, Lakshmi KA, Sumanlatha G, Murthy K. CMI in children with scar failure following BCG vaccination. Indian Pediatr 1998; 35: 123-127. 13. Dawodu AH. Tuberculin conversion following BCG vaccination in preterm infants. Acta Pediatric Scand 1985; 74: 564-567. 14. Kebede F. Tuberculin conversion after BCG vaccination. Ethiop Med J 1993; 31: 264-270. 15. Vidal ML, Hortelano JG, Roman E. Follow-up of BCG through Mantoux reaction. In: Mycobacteria of Clinical Interest. Ed. Casel M. Amsterdam, Elseiver Science Publishers BV, 1986; pp 130-132. 16. Pouchot J, Grasland A, Collet C, Coste J, Esdaile JM, Vinceneux R. Reliability of tuber culin skin test measurement. Ann Int Med 1997; 126: 210-214. 17. Singh M. Nomenclature and definitions. In: Care of the Newborn. New Delhi, Sagar Publications, 1996; pp 1-4. 18. Sedaghatian MR, Kardouni K. Tuberculin response in preterm infants after BCG vaccination at birth. Arch Dis Child 1993; 69: 309-311. 19. Manerikar SS, Malaviya AN, Singh M, Rajgopalan P, Kumar R. Immune status and BCG vaccination in newborns with intrauterine growth retardation. Clin Exp Immunol 1997; 26: 173-175. |
Indian Pediatrics 1999;36: 944-946 |
Reply |
In a baby given BCG but without scar, it is possible that the vaccination was unsuccessful due to defective vaccine or faulty procedures. The absence of scar does not help us to differentiate between the baby with no immune response and the one with immune response in the absence of a scar. One could use the PPD test to try to ascertain the immune status. If PPD reaction is of reasonable dimensions (5 mm or more), one could attribute it to BCG response. Even if PPD response was negative, there could have been some immunological response to BCG. Thus, if BCG was given, the baby developed no scar, and the PPD re-action was negative, the above logic would suggest that the baby could have developed immune response. That is correct, but not always. Suppose the BCG vaccine contained only dead bacilli; there would be no scar and no PPD response. In other words, it is simple enough to repeat the BCG vaccination rather than remain in the dark about the response. We only assume that the BCG vaccination might have been unsuccessful in the asbence of scar when we recommend repeat BCG. The opposite assumption is more risky than the assumption that leads to one more attempt. Scar is a better surrogate of successful immunization than the history of having given BCG. The authors have correctly pointed out many problems with the PPD test, the measurment of response and also the inter-pretation of the result. These are all very true. What they have not addressed is the fact that even the development of CMI is not necessari-ly a reliable surrogate of protection. A lot of skepticism about the need or value of BCG vaccination had arisen due to this observation. As there is good evidence that BCG vaccination does offer good protection against those forms of tuberculosis that devleop largely in the absence of previous experience with Mycobacteria (CMI being the simplest surrogate), and not against those forms of disease that develop in spite of, or actually due to, previous experience and immune response (such as CMI), the Academy recommends BCG vaccination routinely. The Academy does not promote BCG for public health, that is to reduce the transmission or incidence of infection or disease. We have seen a decline in the frequency with which we admit children for tuberculous meningitis but the incidence of adult tuberculosis has not fallen. We believe that this dichotomy is partly at least due to the successful BCG program and the unsuccessful TB control program. It may also be partly due to better nutrition of young children. The authors reviewed the literature and concluded that "it is not known whether the vaccine is as immunogenic or protective in infants who suffer from prematurity and/or IUGR as compared to appropriate for gestational age babies". What surprises me is that instead of using their analytical skill and knowledge to suggest how best to go about giving BCG vaccination to premature and IUGR babies, they ask for "evidence based scientific reasons" for deciding when to give BCG in situations of low gestational age and low birth weight. As Chairman of the Committee on Immunization I would have very much welcomed the opinions of the authors themselves in this matter. Since evidence is said to be unavailable, I shall attempt a logical approach to develop guidelines for practical purposes rather than for debate. Why is BCG given to the neonate? The authors seem to be under the impression that BCG is given to the neonate because the neonate is vulnerable to infection during the early weeks of life. They state that "if BCG is given at 6 weeks, to minimize hospital visits, the baby remains vulnerable to acquire tuberculosis for longer period, as 8-12 weeks are normally required for development of immunity". The neonate and young infant are vulnerable but not exposed under ordinary circumstances. Only when the mother has cavitory tuberculosis is the young infant exposed and clear guidelines have been formulated to manage this situation(1). Otherwise, the cumulative burden of infection (measured by the surrogate of PPD reaction) and of disease (primary tuberculosis) are of the order of about 2% by age 5 years. So then, why neonatal BCG? In the case of neonatal OPV, I had made the original recommendation since we were seeing poliomyelitis in young infants before they could be given sufficient number of doses of OPV. But, I had to show that OPV would be immunogenic in the newborn and that was my contribution to show that the neonate could be immunized as successfully as any older infant. In the case of Hepatitis B immunization, the neonate needs protection either from vertical or from early horizontal transmission from a virus carrier mother and it has been shown that the vaccine is immunogenic in the neonate even in spite of maternal antibody or administered immune globulin. In India, on the average, 4-5% mothers are virus carriers. In the case of BCG, the need for protection is not urgent, but the vaccine takes in the neonate as well as in the older infant. Since the vaccine can be given at this age (unlike DPT, measles vaccine, etc.), the convenience of easy contact with the health worker is the main reason for the recommendation of neonatal BCG. Therefore, in situations of pre- maturity or IUGR, BCG may be delayed until the infant is stabilized, is growing well and weight gain is reasonable. Instead of evidence based answers, I shall answer the questions using common sense and the above background information, as follows. In general, any low birth weight baby may be given BCG as the baby is ready to be sent home. In terms of minimum gestational age, about 38 weeks may be satisfactory provided the baby has reasonable weight (such as about 1800 g or more) and the baby is ready for going home. With less gestational age, we can wait for chronological age and weight to catch up to those necessary for sending the baby home. Babies weighing less than 1200 g are usually not sent home until they have gained some weight and thus the chronological age would be accordingly considered. When they are ready to be sent home, the chronological age would have been 38 weeks equivalent and weight at least 1800 g. When the gestational age was 26-32 weeks, babies post conception are kept in the hospital along with the mothers, until they become stable and growing well. When they are ready to be sent home, that is when weight is about 1800 g and age has reached about 38 weeks equivalent, they could be given BCG. Some neonatologists might consider sending a stable baby home at weight as low as 1500 g but perhaps for such babies the priority is not to give early BCG but to wait until the weight has caught up to about 1800 g. In all these suggestions I have tried to balance the need to wait until the baby's immune system is robust enough, for which purpose it is better to delay vaccination and not to miss the opportunity of the baby being available for vaccination just before sending home. The authors seem to be under the impression that once BCG is given, the other vaccines must be suitably delayed. They state: "If BCG/OPV zero dose is delayed by 3-4 weeks (for babies with very low weight), further vaccination gets progressively delayed, thus keeping the baby at risk to acquire all the dangerous infections for a longer period". Irrespective of when BCG was given any baby who is doing well can be given DPT about 6-8 weeks after birth. The reason for 6-8 weeks interval is for the maternal antibody to decline, and for no other reason. DPT and OPV may be given concurrent with BCG or at any convenient interval after (or even before if need be) giving BCG. T. Jacob John, 2/91 E2 Kamalakshipuram, Reference 1. Consensus statement of IAP working group. Treatment of childhood tuberculosis. Indian Pediatr 1997; 34: 1093-1096. |
