Ind. J. Tub., 1990, 37, 63 RISK OF PULMONARY TUBERCULOSIS ASSOCIATED WITH EXOGENOUS REINFECTION AND ENDOGENOUS REACTIVATION IN A SOUTH INDIAN RURAL POPULATION-A MATHEMATICAL ESTIMATE* V.V. Krishnamurthy 1 and K. Chaudhuri 2 Summary : It has been reported that a substantial proportion of the new cases arise from the previously infected population. Hence, it appears that exogenous reinfection and/or endogenous reactivation play a major role in the development of post-primary disease. Though the risk of disease due to recent infection is known, the risk of disease associated with exogenous reinfection and endogenous reactivation has not been computed in Indian conditions. The data collected during a longitudinal study by NTI, Bangalore was analysed to estimate the above mentioned risk rates. The risk of disease associated with exogenous reinfection was 6.55% per year compared with 0.21% yearly due to endogenous reactivation. To test the validity of the computed risk rates these were applied to the interval between the 3rd and 4th surveys. It was then estimated that 64 new cases should have been diagnosed in that survey interval as against 57 cases actually diagnosed. It was also estimated that 1.9% of the total population would be having recent infection, 1.3% would be previously infected with recent infection and 32.7% with previous infection but no recent infection leaving 64.1% who are not infected at all (uninfected). Among the new cases diagnosed, 28% would have progressive primary disease, 41% cases arise due to exogenous reinfection and 31% due to endogenous reactivation. In other words, the 1.9% population with recent infection contributes 28% of the total new cases, the 1.3% reinfected population contributes 41% and the 32.7% infected population wi thout further reinfection contributes the remaining 31% of the total new cases. Introduction It is estimated that about one third of the Indian population are infected with M.tuberculosis (National Tuberculosis Institute, 1974). It is also reported that about 75% of the total new pulmonary tuberculosis cases are diagnosed from the previously infected and 25% from the uninfected persons (Krishnamurthy et al., 1976). The new cases arising from the previously infected population may have developed the disease either due to exogenous superinfection/reinfection (EXRI) or endogenous reactivation (ENRA). On the other hand, new cases from the uninfected population arise following a comparatively recent primary infection. As a substantial proportion of the new cases are diagnosed from the previously infected persons, EXRI and/or ENRA should be playing a major role in the development of post-primary disease. Though the risk of disease among the previously infected persons is five times that among the uninfected, the risk of disease associated with EXRI and ENRA is not known in Indian conditions. In this analysis, an attempt has been made to mathematically estimate the above mentioned risk rates for the Indian population aged five years and above. Materials and Methods The data collected from four epidemiological surveys during a longitudinal study of tuberculosis in a rural population of South India is analysed (National Tuberculosis Institute, 1974). As the interval between the I-II and II-III surveys was identical (1½ years), the data collected during the first three surveys are analysed. For the details of the survey procedures, the above cited study may be referred. Persons having normal chest x-ray or those with abnormal chest x-ray in the preceding survey(s) but bacteriologically negative who became culture positive with persisting X-ray abnormality in the subsequent survey were termed new cases. Infection occurring within 1½ years is considered as new infection or reinfection, as the case may be. New cases arise from three different groups of population viz., * Paper presented at the First Joint Conference on Tuberculosis and Chest Diseases held at Madras in December, 1989. 1. Statistical Assistant, National Tuberculosis Institute, 8, Bellary Road, Bangalore 560 003. 2. Director, National Tuberculosis Institute, Bangalore. 64 V.V KRISHNAMURTHY AND K. CHAUDHURI 1. Previously uninfected population with recent infection or the newly infected (NI) -progressive primary tuberculosis, 2. previously infected population with added recent infection (RI) -exogenous tuberculosis (from superinfection or reinfection, "reinfection" hereafter) and 3. Previously infected population with no recent reinfection (NRI) -endogenous tuberculosis (as a result of reacti- vation). The formulation of the three groups at the II survey is shown in the accompanying diagram. The development of new pulmonary tuberculosis from the above cited three groups could be mathematically written as: NI × A + RI × B + NRI × C = Total new cases where A, B and C are the risks of disease associated with new infection, reinfection and endogenous reactivation respectively and the abbreviations NI, RI and NRI are as explained above. The first term in the above equation viz., NI x A is equivalent to the total new cases arising from the group of persons with recent infection. If cases diagnosed from the newly infected population could be identified and removed, then the above equation reduces itself to : RI × B + NRI × C = New cases arising from the previously infected population. When the size of RI and NRI groups becomes known, there will be two unknowns i.e. B and C in the equation. By formulating two equations, the values of B and C could be worked out. Findings Size of the population with "recent reinfection (RI) " and "no recent reinfection (NRI) " To estimate the size of RI and NRI, it is assumed that the risk of infection is uniform for the population as a whole, comprising both infected and uninfected persons. Similar assumption has been made by other workers also (Sutherland, 1973). The incidence Diagram showing groups of Population by status of tuberculous infection Population at I Survey Not infected At II Survey Infected At II Survey Not infected Recently infected NI Reinfected RI No Reinfection NRI New cases Primary Tuberculosis New cases due to endogenous reactivation New cases due to exogenous reinfection RISK OF PULMONARY TUBERCULOSIS 65 rate of infection (column 4) between I and II and II and III surveys is available from the already reported five year study, (National Tuberculosis Institute, 1974). By applying these incidence rates to the infected population, the respective sizes of RI and NRI can be estimated. It was estimated that among 10,565 persons (aged 5 years and above) infected at the I survey and examined at the II survey, 415 persons had become reinfected between I-II surveys and I0,150 had no reinfection (Table 1). The corresponding figures for II-III surveys were 229 and 9,165 persons respectively (Table not presented). Among the 70 new cases diagnosed at the II survey, 48 cases were diagnosed from the group of infected persons at I survey, 19 cases from the uninfected (the tuberculin sensitivity status at I survey was not available for three cases). The corresponding figures for the new cases diagnosed at the III survey were 34, 5 and 1 respectively. Two equations are: Between surveys I-II : 415 x B + 10150 C = 48 Between surveys II-III : 229 x B + 9165 C = 34 Solving the two equation : The value of B = 0.0655 or 6.55% The value of C = 0.002108 or 0.21% To test the validity of the risk rates computed above (6.55% and 0.21%), these rates were applied to the interval between III and IV surveys. It was found that 64 new cases could have been diagnosed as against 57 actually diagnosed. The risk of disease associated with the cited different types of tuberculosis infection is given in Table 2. The risk of disease associated with reinfection is 31 times that for endogenous reactivation and twice that for recent infection. Table 2. Risk of disease associated with different types of infection Type of infection Risk of disease (%) (Annual) Recent infection 3.19* Exogenous reinfection (Reinfection) 6.55 Endogenous reactivation 0.21 * Krishnamurthy et al With the information on the size of previously infected population, with or without recent reinfection, it is possible to construct the profile of the population in respect of tuberculous infection (Table 3). The table is self explanatory. Among the infected persons (11, 161), 5% were initially uninfected but got recently infected between surveys I and II (596), 4% were reinfected (415) and 91% (10,150) had no reinfection. Table 1. Size of the population with or without recent reinfection between I and II surveys (estimated) Examined at II survey Previously infected Among I survey Incidence rate of infection (%) between* Age at I survey Uninfected Infected I and II surveys Plus recent reinfection (RI)** No recent reinfection (NRI)** 1 2 3 4 5 = 3 x 4 6 = 3-5 5-14 10194 1409 1.78 25 1384 15-34 6093 4057 3.35 136 3921 35+ 4205 5099 4.99 254 4845 All ages (5 +) 20492 10565 - 415 10150 *National Tuberculosis Institute (1974); **estimated 66 V.V KRISHNAMURTHY AND K. CHAUDHURI Table 3. Population aged 5 years and above (examined at I and II surveys) at II survey by infection status Status of tuberculous infection Number % to total population remain uninfected 19896 64.1 *Uninfected } recently infected 596** 1.9** Previously infected with recent reinfection 415 1.3 Previously infected with no recent reinfection 10150 32.7 Total population 31057 100.0 * Total uninfected = 20492; ** National Tuberculosis Institute, 1974 Among the 67 new cases diagnosed at the II survey, for whom tuberculin sensitivity was known at I survey, 28% had progressive primary tuberculosis, 41% had disease due to exogenous reinfection and the remaining 31% due to endogenous reactivation (Table 4). Contribution by different groups of population to the total new cases at the II survey Population with recent infection constituting 1.9% of the total population have contributed 28% of the total new cases (progressive primary disease); infected population with reinfection constituting 1.3% of the population have contributed 41% of the new cases (disease due to exogenous reinfection), and tie remaining 31% of the total new cases (disease due to endogenous reactivation) have come from the population previously infected with no reinfection constituting 32.7% of the total population (Fig. 1). It could be seen that the infected population with reinfection are not only at the highest risk of developing fresh pulmonary tuberculosis (6.55%) but they make the RISK OF PULMONARY TUBERCULOSIS 67 Table 4. Composition of new cases diagnosed at II survey Type of infection No. of persons Risk of disease (%) New cases % to total new cases Recently infected 596 3.19* 19 28 Previously infected with recent reinfection 415 6.55 27 41 Previously infected with no recent reinfection 10150 0.21 21 31 * Krishnamurthy et al. highest proportional contribution to the total new cases arising in the community. More over, the newly infected persons together with the group of population previously infected and recently reinfected together contribute 69% on the total new cases arising in the community. Only 31% of the new cases arise from the previously infected persons with no recent reinfection, presumably due to endogenous reactivation. Acknowledgement The authors are grateful to Dr A.K. Chakraborty, Deputy Director, CGHS, Bangalore for his comments and suggestions at the draft stage of the paper, Mrs.Anuradha for statistical assistance, Miss T.J. Alamelu for secretarial help and Mr B.R. Narayana Prasad graphics. References Krishnamurthy, VV, Nair, SS, Gothi, GD, a Chakraborty, AK. Incidence of Tuberculosis among newly infected population and in relation to the duration of infected status; Indian Journal of Tuberculosis 1976, Vol. 33/1, 3. National Tuberculosis Institute, Bangalore. Tuberculosis in a rural population of South India : a five year epidemiological study, Bull World Health Orgn, 1974, 51, 473. Sutherland, I. Endogenous reactivation and exogenous reinfection, IUAT 1972,47,123. . Ind. J. Tub., 1990, 37, 63 RISK OF PULMONARY TUBERCULOSIS ASSOCIATED WITH EXOGENOUS REINFECTION AND ENDOGENOUS REACTIVATION IN A SOUTH INDIAN RURAL. made to mathematically estimate the above mentioned risk rates for the Indian population aged five years and above. Materials and Methods The data