|DR. P.R.J. GANGADHARAM ENDOWMENT ORATION
|Year : 2014 | Volume
| Issue : 1 | Page : 44-50
My journey with epidemiology of tuberculosis
Vineet Kumar Chadha
Head, Epidemiology and Research Division, National Tuberculosis Institute, Bangalore, Karnataka, India
|Date of Web Publication||1-Feb-2014|
Vineet Kumar Chadha
Epidemiology and Research Division, National Tuberculosis Institute, Bangalore, Karnataka
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Chadha VK. My journey with epidemiology of tuberculosis. J Mahatma Gandhi Inst Med Sci 2014;19:44-50
At the outset, I am grateful to the Kasturba Health society and this prestigious institute-a shining example of providing community-oriented quality medical education to several generations and excellent and affordable health care besides many significant contributions in community-based research. I will remain indebted to Mrs Shakuntla Gangadharam for instituting this award and I am particularly thankful to Dr. Mrs. Prathiba Narang with whom I have a long professional and personal association for inviting me to be present here today. For me, it is a privilege to deliver an oration in honor of Dr. P.R.J. Gangadharam whose many contributions in control clinical trials, monitoring of drug compliance, scientific basis of intermittent therapy among many others laid the very foundation of TB-control strategies.
I have been involved with the TB-control program for last 20 years. Among other tasks assigned to me from time to time, I have spent majority of my time undertaking TB epidemiology and operational research all over the country. My journey with epidemiology of tuberculosis (TB) commenced when I joined the National Tuberculosis Institute, Bangalore (NTI) in January 1995 and I have found this voyage to be very fascinating and exciting. As you may be aware, NTI has been providing leadership in the study of TB epidemiology right from its inception in 1959.
My induction into NTI started with a case-control study of BCG efficacy among children. The study was planned in the background of zero percent efficacy of BCG against pulmonary TB in adults observed during the famous Chingleput trial.  Although, studies elsewhere in the world had demonstrated efficacy of BCG to confer protection against childhood forms of TB, no such data was available from India. A case-control design was considered more appropriate as a randomized control trial would have been unethical and a cohort study would take many years to complete. Children presenting with suggestive symptoms/signs of TB at two tertiary care hospitals in Bangalore city were assessed for history of contact with a TB case, nutritional status, tuberculin skin test (TST), chest X-ray, examination of sputum/gastric aspirate by smear microscopy and culture, and other investigations to rule out extrapulmonary TB. For diagnosis of TB, Steagen Jones (SJ) scoring method was slightly modified to adapt to Indian conditions. Any child having a score of 7 and above was diagnosed to be suffering from TB. Children residing in the neighborhood with a score < 5 were considered as controls. BCG vaccination status was based on elicitation of a typical BCG scar. After excluding children with doubtful BCG scars, 113 cases and 109 controls were considered for analysis. Efficacy of BCG for all forms of TB in children was estimated at 31%; it was higher for extrapulmonary TB (EPTB) at 37%.  The 15-year follow-up data from Chingleput trial published later revealed an efficacy of 27% against bacillary forms of TB in children.  Even these low levels of efficacy provided support for continuation of the BCG vaccination.
Another opportunity to study TB epidemiology came by way of a community-based survey among children (0-14 years) in 60 peri-urban villages around Bangalore city which was in progress at the time of my joining NTI. Study procedures involved elicitation of symptoms suggestive of TB by interviewing parents of children, assessment of nutritional status, TST, X-ray chest using a mobile Mass Miniature Radiography (MMR) unit and collection of two sputum specimen (only among 5-14 years) for microscopy and culture from those having any of the following: presence of symptoms, history of contact with a TB case in the household, tuberculin reaction size of ≥10 mm or any lesion on chest X-ray film. Survey data revealed poor agreement between SJ scoring and scoring method of International Union against TB and Lung Disease  and paved the way for formulating new diagnostic algorithm for childhood TB while doing away with the scoring systems. Thus, the prevalence of pulmonary TB (PTB) was reported for bacteriologically positive TB and radiologically positive TB as such at 150 per 100,000 and 130 per 100,000 children, respectively.  The prevalence of bacteriologically positive TB in children was about one-third of the prevalence in adults estimated in the area during surveys conducted around the same period. This was the last such reported survey among children in view of the requirement of large amount of resources in terms of man power, money, and equipments. Analysis of tuberculin test results revealed the annual risk of tuberculous infection (ARTI) at 1.0%. 
ARTI denotes the probability of acquiring new tuberculous infection (or re-infection) over the course of 1 year. It represents the overall effect of disease burden and efficiency of TB-control activities, and surveys for its estimation though very challenging are relatively cheaper and less labor intensive than disease prevalence and incidence studies. ARTI is also a useful indicator of the impact of control programs.
For estimation of ARTI, a representative sample of children is subjected to standard TST by trained testers and readers.  Frequency distribution of reactions is plotted as histogram. TST reaction sizes generally follow a bi-modal distribution with an anti-mode separating the true reactors from cross-reactors. Therefore, for estimating prevalence of infection, all reactions more than the anti-mode are considered as tuberculous. In the absence of a clear anti-mode, the proportions of reactions more than the second mode are doubled and added to the frequency of reactions at the second mode to obtain prevalence of infection. This is called the mirror-image technique. From thus estimated prevalence of infection, ARTI is computed mathematically. Surveys to estimate ARTI are generally carried out among children since ARTI rates among them reflect on recent epidemiological situation. Also, higher prevalence of infection with non-tuberculous mycobacteria (NTM) in higher age groups makes the survey data more difficult to interpret.
Most of the information available on epidemiological situation of TB after the National Sample survey (NSS) to estimate prevalence of PTB during 1955-58 pertained to rural areas mostly located in and around NTI and TB Research Centre, Chennai (now National Institute of Research in Tuberculosis). , Therefore, to fill up the gap, NTI first carried out a survey among school children of Bangalore city during 1997-99 which found that the rates of transmission with an ARTI of 1.7% were higher than the surrounding peri-urban villages as observed 4 years earlier. ,
Loaded with this experience, we moved a proposal to conduct a Nationwide ARTI survey. For this purpose, country was divided into four zones - North, South, West and East, each comprising one-fourth of the country's population. The objective was to estimate ARTI separately for each of the zones. These zonal level surveys were carried out with NTI as the nodal center with support of NIRT, New Delhi TB Center (NDTB) and the Mahatma Gandhi Institute of Medical Sciences, Wardha (MGIMS). The surveys were designed to estimate ARTI among 1-9 year old children without BCG scar although children with BCG scar encountered during the registration process were also tuberculin tested. In each zone, the survey was conducted in 600 clusters. The estimated numbers of clusters were allocated to 6-8 districts (selected by PPS -proportional to population size method) in the ratio of population size. Within each district, the clusters were further allocated to rural and urban strata in the ratio of population size. Altogether, 1, 84,992 children were tuberculin test read. The survey findings revealed variation in ARTI rates in the four zones - lowest at 1.1% in South and highest at 1.9% in North; ARTI in West and East zone was 1.7% and 1.2%, respectively.  At the national level, ARTI was estimated at 1.5% which means that out of every 100,000 individuals, 1500 acquire new tuberculosis infection every year adding to the pool of infected people from whom cases would continue to emerge.  This data was used for estimating incidence of TB using Styblo's formula according to which every one percent of ARTI corresponded to 50 new sputum smear positive (NSP) incidence cases per 100,000 population.  Higher rates of transmission were found in urban areas compared to rural areas which highlighted the need for intensifying TB control efforts in the former. Data also revealed that BCG-vaccinated children could be included for tuberculin surveys without any bias on estimates of ARTI. 
Encouraged by the success of the first ever national level ARTI survey, a generic protocol for ARTI survey was prepared by me on behalf of WHO  and I provided technical support for first National/provincial level surveys in Indonesia, Bhutan, and DPR Korea between 2004 and 2009. Results showed significant declines in ARTI rates in Indonesia and Bhutan when compared to data generated during the pre-DOTS era in a few selected districts in the respective nations. ,,, On the other hand, high ARTI rate of 3% found in DPR Korea was instrumental in enhanced funding for intensification of case finding activities there. 
The state and district level surveys in Andhra Pradesh and Orissa revealed ARTI rates more or less similar to the national level. ,, A low rate of transmission was observed in Kerala. 
To find out the trends in epidemiological situation of ARTI, the survey in Bangalore schools was repeated after an interval of 8 years. A yearly decline of 4% was observed in the intervening period. 
A demand for Repeat ARTI surveys at the zonal levels was raised by the policy makers to find out the impact of RNTCP. Leadership to repeat zonal ARTI surveys during 2009-10 was again provided by NTI with support from LRS Institute of TB and Respiratory Disease, New Delhi and Christian Medical College, Vellore besides the Institutes involved in first round of zonal surveys. Altogether 69,496 children were test read. We found out a decline of 4.5% per year at the national level  which was less than 10-15% per year decline observed in other countries under good program conditions, ,, thus suggesting further intensification of control efforts. At the zonal level, while significant declines were seen in North and West, no such decline was observed in South and East. This remains inexplicable though certain hypothesis could be put forth.
The large number of tuberculin surveys also provided us with an opportunity to examine the following clinical aspects of TST:-
- Sensitivity and specificity of different PPD products and dosages
- Influence of BCG vaccination on interpretation of TST in clinical practice
- Influence of nutritional status on TST
- Detection of new tuberculous infection on repeat tuberculin testing
When we were planning for our first National ARTI surveys, 2TU was declared as the standard dose by WHO and IUATLD in view of observations of reduced potency of PPD dilutions prepared in some countries.  Since most experience in India pertained to 1TU PPD RT23, we decided to conduct comparative studies of not only the two doses but also the dilutions supplied by BCG lab, Guindy in Chennai with those from Statens Serum Institute, Copenhagen (SSI). We found no difference in the sensitivity of 1 TU and 2 TU doses and between Guindy and SSI products.  But the specificity was compromised with 2 TU. We also saw no change over the years in potency of 1TU dilutions prepared by BCG laboratory, Guindy. Therefore, a decision was taken to use 1TU dose prepared by BCG lab for the first round of National ARTI surveys. Unfortunately, we were forced to use 2TU for repeat ARTI surveys since Guindy lab ceased to supply PPD and SSI was no longer manufacturing 1TU. However, the estimates of ARTI computed by adopting the mirror image technique were not affected by the usage of different doses of PPD in the two rounds.
We found that about 80% of the children vaccinated with BCG under UIP had TST reactions of < 10 mm.  This was in contrast to earlier observations made during controlled trials and special vaccination campaigns that BCG-induced sensitivity was similar to true tuberculous infection. We also found that BCG-induced tuberculin sensitivity waned with age as also observed during controlled trials. , These aspects may be kept in mind while interpreting TST reactions in vaccinated children.
We also found out that in presence of under-nutrition, TST reaction size was suppressed to the extent of being false negative in about one-third of truly infected children. ,
Studies conducted in NTI have shown that since first TST per se can boost the reaction size to a repeat test, a mere conversion from a size below a certain cut-off pint at first test to more than this cut-off at a repeat test conducted 1.5-3 years apart should not be labeled as a fresh infection unless there is a minimum increase of 10 mm at the second test among those uninfected at first test. ,
Estimation of TB disease burden has always been a challenge for program planners. Since I joined the TB program, three expert groups have been constituted at different points of time where I was a member. The second such group during a meeting in 2005 took note of the declining trend in prevalence of TB during serial surveys in Thiruvallur by NIRT, after implementation of RNTCP.  It was suggested that such surveys be planned at more sites across the country. The baseline surveys have since been carried out during 2008-10 among persons 15 years and above in age by the institutes that volunteered, in Rural Bangalore (NTI), Wardha (MGIMS), Jabalpur (Regional Medical Research Centre, Jabalpur), Mohali (PGI, Chandigarh), Faridabad (AIIMS, New Delhi), Kanpur and Banda (JALMA, Agra). Thus surveys were carried out at altogether 8 sites (district/sub-district level) including Thiruvallur, using a generic protocol. The field staff for each site was trained in a uniform manner at NIRT. The eligible residents in selected clusters were screened for presence of symptoms suggestive of PTB at all sites and additionally by X-ray at three sites - Rural Bangalore, Wardha, and Thiruvallur. Two sputum specimens were collected for microscopy and culture from each of the persons having symptoms/any abnormal pulmonary shadow. The number of individuals registered at different sites varied between 55,000 and 100,000 depending upon whether only symptoms or both screening tools were employed. Based on results from three sites where both screening tools were used, the multiplication factor to correct for non-screening by X-ray was estimated at 1.3. 
In rural Bangalore, we found the prevalence of bacteriological PTB (positive on smear and culture) at 254 (CI: 204-301) per lakh population; prevalence of smear-positive PTB was 108 (CI: 82-134) per lakh population.  There was a decline of 63% from the prevalence estimated in the same area during a survey in 1975. 
We, at NTI, were assigned the task of analyzing the data uniformly for all the sites. The national level prevalence (all ages, all types) was estimated during a meeting of the third expert group which also consisted of WHO experts by adding to the pooled prevalence of bacteriological PTB, the components of extra pulmonary TB in adults assumed at 18% of PTB and pediatric TB at 7% of all adult TB. It was thus estimated at 256 (CI: 161-373) for the year 2010. 
During the prevalence survey in Rural Bangalore, an ARTI survey was also carried out in the same area. The survey revealed that every single prevalent smear positive case infects 10 persons each year which was the same as in the pre-RNTCP era.  This, despite the increased case detection and treatment success rates in RNTCP era, could be attributable to the delay in diagnosis as observed during internal evaluations conducted by Central TB division. This finding suggests renewed efforts to cut down delay in diagnosis with more intensive involvement of the private sector.
Estimating incidence has always been even a bigger challenge. Hitherto, estimates in India were based on Styblo's formula. It has now been universally accepted that this formula is not applicable in DOTS era. This has been further corroborated on correlating the results of repeat ARTI surveys and RNTCP case notification rates.
Therefore, the third expert group estimated the incidence for the year 2010 using 'Onion model' approach. In this method, the total proportion of patients missed from notification data is estimated by adding the proportions missed due to various factors - lack of access, not seeking care despite having access, missed diagnosis in spite of presenting at health facilities, diagnosed by non-RNTCP and RNTCP providers but not notified. The proportions missed at different stages were estimated while taking into consideration the limited available data and personal experience. We thus estimated the incidence for all TB cases at 2.2 million (CI: 2.0-2.5) @ 184 (CI: 165-204) per lakh population per year. 
The same group as above estimated the TB mortality rate in India at 26 (CI: 17-39) per lakh population per year by pooling the data from four verbal autopsy studies carried out in different parts of the country. 
As the community-based studies are too expensive and labor intensive, we need to develop innovative and sustainable approaches for monitoring TB situation and its epidemiological trends. We, at NTI, piloted 'capture -recapture' modeling approach in a district of Karnataka. Besides RNTCP data, two independent sources on patients diagnosed and /or treated by two different sources were generated prospectively in individual departments of a medical college as one source and all nursing homes/polyclinics as the other source. Using distribution and overlap of TB cases from the three sources, log linear 'Capture-recapture' analysis was undertaken to estimate the number of TB patients not found in any of the three sources. We found the level of under-reporting (unpublished data) to be in consonance with the data available from a community based survey in 30 districts and the estimate of incidence in the district was similar to the present estimate of incidence at national level.  This suggests that it is feasible to apply this approach at state/national levels. The recent launch of 'NIKSHAY, by the Central TB Division is a welcome step in this direction.  The case based data entry of patients registered under RNTCP on NIKSAY website which also has the provision for notification by non-RNTCP providers will make the capture recapture analysis really cost effective and sustainable to estimate incidence in each of the states in the years to come.
Besides, I have recently developed two models for estimating incidence of childhood TB and TB mortality rate in India. For incidence of pediatric TB, risks of disease following primary infection in different years of age available from a systematic review  were applied to the current ARTI rates. Same rates of development of the disease were applied for re-infection. Disease rates due to re-activation have been available from published data.  The incidence of childhood TB was estimated at 89-150 per lakh children and the proportion of pediatric TB out of all TB was estimated at 17-24%.
TB mortality rate was estimated using RNTCP data on treatment outcome among new cases, their fate after 2.5 years as available through studies, proportion registered for re-treatment and their outcome and fate after 2.5 years. , Treatment outcome of the proportion of patients treated in the private sector was available from two areas as published data  and same rates of mortality in 2.5 years after treatment as determined among RNTCP patients were applied. The risk of death in untreated cases was available from a systematic review.  TB mortality thus estimated was at 13.1 per lakh population per year.
These are of course preliminary outputs of the modeling work which we intend to take it further with necessary support of other TB workers, epidemiologists, and statisticians. We eagerly look forward to Central TB Division which has proposed a modeling group for not only estimating epidemiological situation of TB and its trends but also for utilizing the modeling techniques for program-related decision making.
I once again thank the organizers for giving me the opportunity to share my experiences in TB epidemiology. I thank everyone present here for their patient listening. Last but not the least, I wish to convey my sincere thanks from this platform to all the institutes that collaborated with NTI in various studies, NTI faculty and the non-medical officials of especially epidemiology, statistics, and laboratory sections, NTI without whose support this journey would have not been possible.
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| Authors|| |
Dr. P.R.J. Gangadharam annual award has been initiated by Mrs. Sakunthala Gangadharam in the fond memory of her husband for any Indian scientist who has significantly contributed towards the cause of tuberculosis. The Kasturba Health Society and the members of the Mahatma Gandhi Institute of Medical Sciences, Sevagram conferred this privileged award for the year 2013 to Dr. Vineet Kumar Chadha for his outstanding contributions in TB control, understanding of TB epidemiology and as a trainer in all aspects of TB for over 20 years.
Dr. Vineet Kumar Chadha was Assistant Director General (TB), Ministry of Health and Family Welfare, New Delhi during 1994-95 and is presently working as Public Health Consultant and Head of Epidemiology & Research Division, National Tuberculosis Institute, Bangalore. He has the distinction of developing generic guidelines on behalf of WHO for estimating Annual Risk of Tuberculosis Infection (ARTI), leading two national level ARTI surveys and supporting many countries in epidemiological studies. The text of his oration is as below.