Tuberculosis in Children and Young Adults Clydette Powell, MD, MPH USAID/Washington CCIH, May 2004 Good Morning and welcome. It gives me great pleasure to begin our conference on research priorities in pediatric TB with a discussion on the global epidemiology of childhood tuberculosis.

Objectives Overview global epidemiology Review available surveillance data and epidemiologic studies Review TB and HIV association Assess data limitations Provide recommendations for future data collection and research This presentation will start with a brief global overview and then focus on the available information on TB among children less than 15 years of age, as this is the standard WHO definition of childhood TB. I will begin with a review of the available surveillance data worldwide on childhood TB. Next, I will review epidemiologic studies of trends in childhood TB as well as risk factors for TB in children. The limitations of these data sources will be discussed. Finally, I will suggest some recommendations for future priorities in data collection and epidemiologic research.

Tuberculosis A Global Emergency One third of the world’s population is infected TB kills 5,000 people a day – 2-3 million each year HIV and TB co-infection is producing explosive epidemics Hundreds of thousands of children will become TB orphans this year MDR threatens global TB control It is estimated that one-third of the world’s population is infected with Mycobacterium tuberculosis, and that TB kills 5000 people a day or between 2 and 3 million people each year. The combination of HIV and TB coinfection is producing explosive epidemics. Hundreds of thousands of children will be orphaned this year when their parents and caretakers die from TB. Finally, multi-drug resistant TB, or MDR, is threatening global TB control.

Background Tuberculosis (TB) is increasing among adults in many areas TB is major cause of childhood morbidity and mortality worldwide Limited information on epidemiology of TB in children There is ample evidence that TB among adults is increasing in many areas of the world. TB is an important cause of childhood morbidity and mortality worldwide, although it has been a lower public health priority in recent years. There is limited information on many aspects of TB in children, including the epidemiology of TB.

Childhood TB Why neglected? Why is it important? Not considered important in global program or contributing to immediate transmission Not regarded as public health risk Difficult to diagnose Why is it important? Health problem in children May later contribute to epidemic

Leading Infectious Disease Causes of Death, 1998 3.5 2.3 2.2 1.5 1.1 0.9 TB is among the leading causes of death for all ages worldwide. While infections with and deaths due to HIV/AIDS are on the rise in many countries, many of these individuals are coinfected with TB, and in fact also frequently die from TB. WHO Report 2000

TB in Children WHO estimate of TB in children 1.3 million annual cases 450,000 deaths 15% of TB in low-income countries children vs. 6% in United States In 1989, the World Health Organization, or WHO, estimated that there were 1.3 million annual cases, and 450,000 deaths due to tuberculosis among children less than 15 years of age. Unfortunately, these estimates have not been revised more recently. It is estimated that 15% of all TB in low-income countries occurs among children less that 15 years of age compared with only 6% in the United States, and even lower percentages in some European countries.

Childhood TB as Sentinel Event Indicates recent transmission in a community Rapid progression from infection to disease “A deterioration in the control of TB thus immediately hurts the youngest generation” (Rieder, 1997) Children are future reservoir of disease Despite the relative neglect of the subject, a case of childhood TB has been described as a sentinel event, because it indicates recent transmission of M. tuberculosis in a community. Because there can be rapid progression from infection to disease in young children, it has been said that “A deterioration in the control of TB thus immediately hurts the youngest generation.” Further, children represent the future reservoir of disease. Thus, any effort to control the burden of TB over the long term needs to consider the role of infection and disease in children. Rieder H. Anales Nestle, 1997

Effect of HIV? 700 600 Male Female 500 400 300 Per 100,000 population 200 100 Male Female Per 100,000 population <1 1-4 5-9 10-14 15-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54 Age (years) Effect of HIV?

Childhood TB diagnosed by: Combination of : Contact with infectious adult case Symptoms and signs Positive tuberculin skin test Suspicious CXR Bacteriological confirmation Serology

Risk factors : infection to disease HIV Malnutrition Recent exposure Young age Short incubation period More severe Highest risk More difficult to diagnose Host factors Effect of HIV?

Risk Factors for TB - U.S. Racial/ethnic minorities Foreign-born children or children of immigrant families Internationally adopted children Children traveling overseas Poverty and crowding Contact with infectious adult case In this final section, I would like to discuss risk factors for TB in children from published studies in the literature. As was shown on a previous graph of surveillance data from the United States, children who are racial or ethnic minorities have a higher risk of TB. Children who were foreign born or born to immigrant families also have a higher risk of TB. In addition, children who are adopted internationally or who travel overseas have a higher risk of TB infection and disease. Finally, poverty and crowding contribute to TB in children. One of the strongest risk factors for TB in a child is contact with an infectious adult. In several studies in the US, more that half of all childhood cases of TB were found through contact investigations of infectious adults.

Tuberculous Infection Among Children by Type of Contact and Bacteriologic Status of Index Case, British Columbia and Saskatchewan, 1966-1971 Close Percent infected Close Casual Casual Grzybowski S, et al. Bull Int Union Tuberc 1975;50:90-106

Risk of Progression to Disease Age 43% in infants (children < 1year) 25% in children aged one to five years 15% in adolescents 10% in adults Recent Infection Malnutrition Immunosuppression, particularly HIV Once infected, certain risk factors increase the risk of progression to TB disease. A strong risk factor for disease is age of infection, with infants having a 43% risk of disease progress, children aged 1 to 5 a 25% risk of progress, and adolescents a 15% risk of disease progress. Adults, by contrast, have a 10% lifetime risk once infected. Recent infection, including among adults, is another risk factor for disease progression, as is malnutrition and immunosuppression. Immunosuppression due to the human immunodeficiency virus, or HIV, is the most potent risk factor for disease progression now known among adults. In the remainder of this talk, I will focus on TB DISEASE in children Miller, 1963

Challenges for Surveillance Difficult diagnosis of childhood TB Lack of standard case definition Increased extrapulmonary disease Low public health priority of childhood TB There are many challenges to the surveillance of childhood TB. They include the difficult diagnosis of TB in children which often relies on clinical algorithms or checklists instead of bacteriologic confirmation. In published studies and surveillance systems, there is not a standard case definition of childhood TB. Children, particularly young children, are more likely to have extrapulmonary disease which can also be more difficult to confirm bacteriologically. Finally, because many children are not smear-positive, and therefore not as infectious, childhood TB has been given a low public health priority in comparison with other aspects of TB control.

WHO Estimated Total Cases by Age, 2000 Country Total Cases Cases <15 yrs % in Children India 1,815,740 185,233 10.2 China 1,645,703 86,978 5.3 Indonesia 581,918 15,691 2.7 Bangladesh 325,110 33,166 Nigeria 261,404 32,310 12.4 Pakistan 244,736 61,905 25.3 Philippines 230,217 12,167 South Africa 220,486 35,449 16.1 Russian Fed. 183,373 7,778 4.2 Ethiopia 178,349 28,675 Dem. Rep. Congo 148,598 24,052 I have abstracted these estimates for the 22 high burden countries and calculated the percent of disease which occurs in children for each country. The results of these estimates are shown on this slide and the next one. I have listed the 22 high burden countries in order of descending total of TB burden. Estimates of cases less than 15 years of age vary from a low of 2,317 cases in Thailand to a high of more than 185,000 cases in India. TB in children accounts for a highly variable percentage of all TB in a given country ranging from a low of 2.7% in Indonesia and Thailand to more than 20% in Afghanistan, Brazil, and Pakistan. In most Sub-Saharan countries, TB in children represented more than 15% of all TB cases. Had approximately 16% of all TB in children.

WHO Estimated Total Cases by Age, 2000 Country Total Cases Cases < 15 yrs % in Children Viet Nam 143,023 7,559 5.3 Kenya 137,603 22,124 16.1 Tanzania 117,489 18,890 Brazil 113,528 23,520 20.7 Thailand 85,928 2,317 2.7 Myanmar 78,489 8,007 10.2 Zimbabwe 76,296 12,267 Uganda 75,250 12,099 Cambodia 75,045 3,966 Afghanistan 69,342 17,540 25.3 Mozambique 47,909 7,703 TOTAL 6,856,537 659,397 9.6 Using this method, there were nearly 7 million total TB cases worldwide in 2000 in the 22 high burden countries, of which nearly 660,000 or 9.6% occurred in children. Using total WHO estimates, there were a total of 884,011 cases in children. The 22 high burden countries accounted for 75% of all TB in children in 2000. While these estimates provide a bench mark, the large variability in the percent of childhod cases by country is surprising, and suggests some countries may significantly underreport childhood cases. These estimates are dependent on the number of smear-positive cases reported to WHO as well as a number of other assumptions which have not been tested.

Childhood TB in Malawi Retrospective study of 43 hospitals using National TB Data from 1998 2739 cases in children (11.9%) 1.3% smear-positive, 21.3% smear-negative, 15.9% extrapulmonary Poor outcomes 45% completed treatment 17% died 13% default 21% unknown A recent study published this year is an excellent example of the possibilities of using surveillance data. In a study in Malawi, a retrospective study was performed using records at all 43 public hospitals which treat TB in Malawi in 1998 and National TB program records. This study found 2739 cases of TB in children, representing nearly 12% of all TB in 1998. TB in children accounted for 1.3% of all smear-positive cases, 21.3% of smear-negative cases, and 15.9% of all extrapulmonary cases during 1998. This analysis also revealed poor outcomes among children: only 45% completed treatment, 17% died, 13% defaulted, and in 21%, the treatment outcome was unknown. Harries AD et al. Int J Tuberc Lung Dis. 2002; 6: 424-31.

Active Case Finding of TB Meningitis South Africa study among children < 15 years Only 56% of cases were registered 16% of all cases in register contained errors Incorrect diagnosis, double notification, clerical error A study from South Africa examined TB meningitis, the deadliest form of TB, among children less than 15 years of age. In this study, researchers found that only 56% of all cases had been properly registered. In addition, 16 percent of all the cases recorded in the register contained errors including incorrect diagnoses, double notification, or clerical errors. Thus, this study found both errors of omission and inclusion in the register. Because TB meningitis is a deadly disease, it may be more likely to be correctly reported. Because this study showed that only 56% of cases of TB meningitis had been correctly registered, it suggests that recording and reporting of childhood pulmonary disease may be even more incomplete. Berman et al. Tubercle. 1992; 73: 349-55.

Extrapulmonary TB in Children Proportion in a given country could be used as measure of case detection 25-44% of all childhood TB in Ugandan study 43% of children in Ethiopian study 21.3% of childhood TB using US surveillance data Several researchers have suggested that the proportion of extrapulmonary TB in children could be used as a measure of case detection. Thus, countries reporting a high proportion of extrapulmonary TB may in fact be underdiagnosing cases of childhood pulmonary TB. A study of TB among hospitalized children in Uganda found that extrapulmonary TB accounted for from 25 to 44% of all TB in children from 1985 to 1989. In a study of 412 cases of both inpatient and outpatient childhood TB in Ethiopia over two years, 43% of all cases were extrapulmonary. By way of comparison, extrapulmonary TB accounted for only 21.3% of all childhood TB in the United States from 1990 to 2000. This proportion has remained stable over time in the US.

TB and BCG Vaccination Efficacy for adult pulmonary TB 0-80% in randomized clinical trials Best efficacy against serious childhood disease 64% protection against TB meningitis 78% protection effect against disseminated TB BCG important for young children, inadequate as single strategy Finally, in the next section, I would like to briefly mention a few topics of importance in understanding the epidemiology of childhood TB: BCG vaccination, TB/HIV coinfection, and drug resistance. BCG has an important, but limited role in the control of TB, particularly childhood TB. While the efficacy of BCG in preventing adult pulmonary TB has varied from 0 to 80% in randomized clinical trials, it has shown the best efficacy against serious forms of childhood disease. In a published meta-analysis of BCG efficacy, it had a 64% protective effect in preventing TB meningitis in children and a 78% protective effect in preventing disseminated TB among children. Clearly, BCG has an important role in preventing serious disease in young children. However, BCG alone is insufficient to prevent children from TB. Colditz GA et al. JAMA 1994; 271: 698-702.

Estimated TB incidence HIV prevalence adults 15- 49 years Relationship between TB and HIV What about children? 800 800 600 600 Estimated TB incidence (per 100 000 population) 400 400 200 200 0.1 0.1 0.2 0.2 0.3 0.3 0.4 0.4 HIV prevalence adults 15- 49 years

TB/HIV Coinfection in Children 11-64% of children with TB are coinfected with HIV in published studies 1-12% of children with AIDS in autopsy studies found to have TB Other lung disease in children with HIV common Difficulty of confirming TB in HIV-infected children may result in overdiagnosis and overreporting The associated risk of HIV and TB coinfection has been well established in adults. However, in children, this association is less clear. Published studies of children with TB have shown HIV coinfection rates of 11 to 64%. Unlike autopsy studies in adults with AIDS showing high rates of TB, several autopsy studies in children with AIDS have shown low rates of TB from 1 to 12%. Children with HIV commonly have other lung disease including pneumocystic carinii pneumonia, lymphoctyic interstitial pneumonia, or LIP, and other viral and bacterial pneumonias. Because it is difficult to bacteriologically confirm a diagnosis of TB in any child, children with HIV infection and lung disease may be overtreated for TB. Children with HIV do develop TB, though it is unclear with what frequency.

Clinical and immunopathological course of HIV associated TB

Treatment questions Difficult to evaluate true cure Recommended same length of treatment as adults HIV & length of treatment?? Many uncertainties eg pharmakokinetics, treatment of MDR-TB Relapse/re-infection in HIV positive children Mortality?

Conclusions Data on trends in childhood TB are limited Consensus needed on common definitions Few epidemiologic studies in children worldwide Additional studies are needed Childhood TB needs to become a priority Data on trends in childhood TB are limited, both from existing surveillance data as well as from the published literature. A consensus is needed to develop common definitions for the study of childhood TB. Few epidemiologic studies have been performed worldwide to assess risk factors for childhood TB as well as for adverse outcomes among children diagnosed with TB. Finally, additional studies in these areas could provide valuable insight into the burden and distribution of childhood TB. As we begin the work of this conference, it will be our task to identify the research priorities for pediatric TB. In order for action to be taken on these recommendations, childhood TB needs to become a larger priority for national TB programs, funders, and other organizations.