Poster # 923

Tuberculosis (TB) in a cohort of Latin American infants and children Data from the NISDI Pediatric Protocol

J A Menezes1, L Freimanis-Hance2, Suzanne Essama-Bibi2, T Abreu3, F Ferreira4, N Pavia Ruz5, B Grinsztejn6, L Serchuck7, R Hazra7, and C Worrell7 for the NISDI Pediatric Study Group 2008 Hospital dos Servidores do Estado, Rio de Janeiro, Brazil1, Westat, Rockville, MD2, Instituto de Puericultura e Pediatria Martagao Gesteira, Rio de Janeiro, Brazil3, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil4, Hospital Infantil de Mexico Federico Gomez, Mexico City, Mexico5, Hospital Geral Nova de Iguacu Setor de DST/AIDS, Rio de Janeiro, Brazil6, and Eunice Kennedy Shriver National Institute of Child Health and Human Development7
ABSTRACT
Background: Tuberculosis (TB) is a major opportunistic infection of HIVinfected persons in Latin America. Accurate measures of the burden of childhood TB are lacking partly because diagnosis of TB in children is difficult. Studies of TB in HIV infected children are clearly needed. Methods: A retrospective study of TB diagnoses was done within the NICHD International Site Development Initiative (NISDI) pediatric protocol, which is a prospective cohort study enrolling HIV-infected (HIV+) and HIV-exposed uninfected (HIV-) children at multiple clinical sites in Latin America. This paper describes the occurrence and clinical manifestations of TB in the cohort of HIV+ children, and the diagnostic methods used. Results: From 2002-2006, 1404 infants, children and adolescents (742 HIV+, 620 HIV-, 42 indeterminate) were enrolled at 15 sites (11 in Brazil, 2 in Mexico, 2 in Argentina). While only 1 case of TB was identified in the HIVgroup, 58 of the HIV+ children had had at least one episode of TB; the majority (53/58) were diagnosed before enrollment. Most of the children were either diagnosed with HIV prior to TB (median 11.4 months) or diagnosed with both conditions within a month of each other (50% and 28% respectively). The diagnosis of TB preceded that of HIV for 22% of children (median 9.4 months; range 4.5-33 months). At diagnosis 15 cases were <1 year old, 24 were 1-4 years, 16 were 5-14 years and 3 were >14 years. The most common clinical presentation was miliary disease (48%). Pulmonary and extra-pulmonary disease were seen in 36% and 16% respectively. The most commonly reported symptoms were fever (60%) and weight loss (33%). Bacteriological evidence alone or in combination with other methods was used in 43% of diagnoses, while clinical and/or radiological evidence were used in 47%. 31% reported contact with a case of TB, usually at home, and 74% had received BCG. 21 had a tuberculin skin test performed and 8 tested positive. TB episodes occurred within 6 months of initiation of antiretroviral therapy in 9 cases, suggesting immune reconstitution. Conclusions: The proportion of affected children with close contact to a known TB case emphasizes the need for adequate contact tracing of adult TB cases. Diagnosis of TB may have indicated HIV infection in as many as half of the cases. Screening for HIV or TB should be performed in children upon diagnosis of either condition. Research on optimizing preventive strategies in TB-exposed, HIV+ children is needed.

Name: Jacqueline Menezes Mailing Address: Hospital dos Servidores do Estado, R. Sacadura Cabral 178 Anexo IV, 4 andar, 20221-903 RIO DE JANEIRO, Brazil Tel: 55(21) 2230018 Fax: 55(21) 22637135 Email: jacqueline@diphse.com.br

OBJECTIVES
To evaluate the occurrence of TB in a cohort of HIV infected infants, children and adolescents from Latin American countries. To describe cases of TB with respect to: Clinical presentation. The temporal association of TB diagnosis with HIV diagnosis. Diagnostic methods. Epidemiological data: 19 out of 58 subjects (33%) reported contact with a known case of TB. In 14/19 (74%) contact occurred at home. In 18/19 (95%) frequency of contact was daily. BCG immunization:

RESULTS
The most frequent signs and symptoms were fever, reported in 60%, and weight loss, reported in 33%. More than half (53%) were hospitalized for the TB episode.
Figure 4. Immune suppression and clinical presentation of TB in HIV-infected children. Clinical presentation in 22 cases for which CD4 results were available near the time of TB diagnosis.

RESULTS
Timing of TB diagnosis with respect to HIV diagnosis and initiation of ART: 50% were diagnosed with HIV first (median 11.4 mos; range 1.2-85.2 mos before TB diagnosis). 28% received both diagnoses within the same month. 22% were diagnosed with TB first (median 9.6 mos; range 4.5-33 mos before HIV diagnosis). 9 TB episodes (16%) occured within 6 months of initiating
4 Number of cases 3 2 1 0 2 1 0 CD4 <15% 0 CD4 15 - <25% 2 4 4 4 Miliary Pulm. Lymph.

METHODS
Study Population A retrospective study of TB diagnoses was done within the NISDI pediatric protocol, a prospective cohort study enrolling HIV-infected and HIV-exposed uninfected children at multiple clinical sites in Latin America. Subjects enrolled from 2002-2006 who had medical records available to sites from the time of TB episodes were included.

43/58 (74%) children received at least one dose of BCG (2 had received 2 doses). Age at BCG was < 1 month in 49% and < 6 months in 90%. Tuberculin Skin Testing (TST): PPD was performed in 21 (40%) of cases; 13 (62%) were negative. Use of Isoniazid preventive therapy (IPT) within the cohort: Only 9 subjects received IPT: 7 HIV+ and 2 HIV-; none of the children who received IPT developed TB disease.
5 5

ART, possibly indicating immune reconstitution syndrome.

CONCLUSIONS
One third of children with TB reported close contact with a known case of TB. None received IPT. Childhood TB reflects recent transmission and

25

24

CD4 >25%

points to inadequate contact tracing within health systems. Diagnosis of TB may have indicated HIV infection in 22% of subjects,

Number of patients

Definitions In presumed TB the diagnosis is suspected based on clinical, radiologic, and/or non-specific laboratory findings, as well as response to empiric treatment; specific tests for M.Tb were negative or not done. In proven TB, the criteria for a presumed case have been met and M.Tb has been detected by a specific test for the organism.

Level of immunosupression

20

15

15

16
<12mo 1-4yr

revealing possible missed opportunities for early diagnosis and treatment Table 1. Diagnostic Methods (all cases).
Bacteriologic alone Radiological alone Clinical alone 1 3 8 16 7

of HIV infection. Diagnosis of HIV could have prompted screening and prophylaxis for TB and might have avoided the development of active TB in some patients. Screening for HIV or TB should be performed in children upon diagnosis of either condition. Research on optimizing preventive strategies in TB-exposed, HIV positive children and improving diagnostic methods are needed.

10

5-14yr >14yr

3 <12mo 1-4yr 5-14yr >14yr

BACKGROUND
Infection and disease due to Mycobacterium tuberculosis (M.Tb) are highly prevalent in the developing world; TB is a major opportunistic infection in HIV-infected people. Infants and children under 5 years of age are at particular risk for infection, disease and death. Data about TB in HIV-infected children are scarce, partly because the diagnosis of TB is difficult in children and even more challenging in HIV-infected patients [1,2,3]. Compared to other countries in the region, TB incidence in Brazil (40.8/100,000) is comparable to that in Argentina (39/100,000), and higher than that in Mexico (21/100,000) [4,5]. Peru, Bolivia, Ecuador, Guyana and Haiti all have TB incidences > 100/100,000 [4,5]. Other studies describing cohorts of HIV infected children with TB have also been retrospective and/or hospital-based (2, 7-9).
Number of Cases

RESULTS
1404 infants, children and adolescents (742 HIV-infected, 620 HIV exposed, uninfected, 42 indeterminate) were enrolled at 15 sites (11 in Brazil, 2 in Mexico, 2 in Argentina) as March 2006. 1 case of TB was identified in the HIV- group (not discussed further). 58 in the HIV-infected (HIV+) group had an episode of TB. 91% of HIV+ TB cases (53/58) were diagnosed before enrollment.
30 25 20 15 10 5 0 Brazil Mexico 15 8 2 3 1 Proven Presumed 29

Clinical and radiological Clinical and Bacteriologic

Figure 2. Distribution of cases by age at TB diagnosis, according to the age ranges used by WHO.

Bacteriologic and Radiologic 1 All three categories No test reported 16 6

REFERENCES
1. 2. 3. 4. 5. 6. 7. 8. 9. Chintu C, et al. Int J Tuberc Lung Dis 2005; 9:477-484 Cohen JM, et al. HIV Medicine 2008; 9:277-284 Corrigan DL, et al. Breathe 2007; 3(4): 351-63 Brasil, (2007) Ministrio da Sade, Programa Nacional de Controle da Tuberculose, Secretaria de Vigilncia em Sade. WHO (2008) Global tuberculosis control www.who.int/tb/publications/global report/2008 accessed 01/02/2009 Rekha B, et al. Pediatr Resp Rev 2007; 8: 99-106 Geoghagen M, et al. CDC West Indian Med J 2004;53:339-345 Viani RM, et al. Int J Tuberc Lung Dis 2008; 12: 411-416 Ramrez-Cardich, et al. Int J Infect Dis 2006; 10:278-281

16 Number of cases 14 12 10 8 6 4 2 0 9

15
Table 2. Chest x-ray results at diagnosis

11 Miliary Pulmon. Lymph. 3 2 1 1 1 >14

Localized infiltrate Hilar/paratracheal adenopathy Miliary infiltrate Multilobar infiltrate Pleural effusion Cavitation

14/35 (40%) 12 /35 (34%) 10/ /35 (29%) 07 /35 (20%) 04 /35 (11%) 03 /35 (9%)

4 2 <12 mo

ACKNOWLEDGMENTS
Funded by:

Argentina

1-4 yr

5-14 yr

Figure 3. Clinical presentation by age at TB diagnosis. Figure 1. Distribution of cases of TB in HIV+ children according to country of origin and whether proven or presumed.

(Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland). Supported by NICHD Contract # HHSN267200800001C (NICHD Control # N01-DK-8-0001). We want to thank the Study Participants, Clinical Sites, the NISDI Executive Committee, and Westat.