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Epidemiology of Pediatric Tuberculosis Using Traditional and Molecular Techniques: Houston, Texas

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Epidemiology of Pediatric Tuberculosis Using Traditional and Molecular

Techniques: Houston, Texas

Susan H. Wootton, MD*; Blanca E. Gonzalez, MD*; Rebecca Pawlak, MS‡; Larry D. Teeter, PhD‡; Kim Connelly Smith, MD, MPH§; James M. Musser, MD, PhD‡㛳; Jeffrey R. Starke, MD*; and

Edward A. Graviss, PhD, MPH‡¶

ABSTRACT. Objective. To investigate the transmis-sion dynamics of pediatric tuberculosis (TB) by analyz-ing the clinical characteristics with the molecular profiles of Mycobacterium tuberculosis isolates during a 5-year period.

Methods. A retrospective review of a prospective population-based active surveillance and molecular epi-demiology project was conducted in private and public pediatric clinics within Houston and Harris County, Texas. The study population consisted of patients who had pediatric TB diagnosed from October 1, 1995, through September 30, 2000. Cases and potential source cases (PSC) were interviewed using a standardized ques-tionnaire. AvailableMycobacterium tuberculosisisolates from cases and PSCs were characterized and compared by IS6110 restriction fragment length polymorphism, spoligotyping, and genetic group assignment. Clinical characteristics were described, and molecular character-izations were compared. Data were analyzed by using EpiInfo 6.02b and SAS 8.2.

Results. A total of 220 (92%) of 238 pediatric TB cases were included. Epidemiologic and clinical findings were consistent with previous studies. Molecular profiles from 3 cases did not match the profile of PSC. Four previously unknown PSCs were identified using molecular tech-niques. Fifty-one (71.8%) of 71 isolates matched at least 1 other Houston Tuberculosis Initiative TB database iso-late and were grouped into 33 molecular clusters. Cases were more likely to be clustered when the patients were younger than 5 years, identified a source case, or were US born.

Conclusions. Traditional contact tracing may not al-ways be accurate, and molecular characterization can lead to identification of previously unrecognized source cases. Recent transmission plays a significant role in the trans-mission of TB to children as evident by the high degree of clustering found in our study population. Pediatrics 2005;116:1141–1147; epidemiology, infectious disease, pe-diatric, tuberculosis.

ABBREVIATIONS. TB, tuberculosis; MTB,Mycobacterium tubercu-losis; TCR, TB Control Registry; HTI, Houston Tuberculosis Initia-tive; TST, tuberculin skin test; PSC, potential source case; RFLP, restriction fragment length polymorphism; OR, odds ratio; CI, confidence interval; CSF, cerebrospinal fluid.

T

uberculosis (TB) continues to be a significant health problem in the United States. Although the total number of cases has declined 44.2% from 1992 to 2003, the population that isⱕ24 years of age accounts for 16% of reported cases in the United States. Houston, ranked fourth among US metropol-itan areas in total number of TB cases in 2002, mirrors national trends with 63 (13.8%) of 456 cases occurring in patients who areⱕ24 years.

In contrast to adults, the diagnosis of pediatric TB is usually established on clinical and epidemiologic grounds as available diagnostic techniques have a low yield in this population.1–3In addition, children are more likely to develop disease from a recent infection (ie, ⬍1 year). Thus, pediatric TB often re-flects recent TB transmission within a community and consequently provides useful markers for mon-itoring and directing TB control programs.4

Conventional contact tracing and molecular anal-ysis are 2 methods that are used to monitor Mycobac-terium tuberculosis (MTB) transmission. Characteriz-ing and comparCharacteriz-ing TB isolates through molecular analysis can identify contacts that are missed by traditional techniques and can estimate the propor-tion of TB that is attributable to recent transmission, otherwise known as clustering.5–12 The aim of this study was to describe the clinical characteristics of pediatric TB in Houston, Texas; to verify source case information for pediatric TB patients using molecu-lar techniques; and to determine the degree of clus-tering among pediatric TB patients.

METHODS

Guidelines of the US Department of Health and Human Ser-vices and from the Institutional Review Board of Baylor College of Medicine and Affiliated Hospitals and the Committee for the Protection of Human Subjects at University of Texas-Houston Medical School were followed in the conduct of the study.

Study Population

From October 1995 through September 2000, the City of Hous-ton TB Control Registry (TCR) identified pediatric TB patients and referred them to the Houston Tuberculosis Initiative (HTI) for enrollment in the study. The HTI is an ongoing population-based active TB surveillance and molecular epidemiology project in From the *Department of Pediatrics, Infectious Disease Section, Baylor

College of Medicine and Texas Children’s Hospital, Houston, Texas; De-partments of ‡Pathology and ¶Medicine, Baylor College of Medicine, Hous-ton, Texas; §Department of Pediatrics, University of Texas-Houston Medical School, Houston, Texas; and㛳Rocky Mountain Laboratories, National Insti-tute of Allergy and Infectious Diseases, National InstiInsti-tutes of Health, Ham-ilton, Montana.

Accepted for publication Feb 4, 2005. doi:10.1542/peds.2004-2701 No conflict of interest declared.

Reprint requests to (E.A.G.) Department of Pathology (209E), Baylor Col-lege of Medicine, One Baylor Plaza, Houston, TX 77030-3498. E-mail: egraviss@bcm.tmc.edu

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Harris County, Texas. Patients were excluded from enrollment when they (1) could not be located, (2) refused the interview, (3) had lived in Harris County for⬍3 months before TB diagnosis, or (4) had incomplete records. The majority of patients were clini-cally evaluated by 1 of 2 authors (K.C.S. or J.R.S.).

Case Definitions

We defined a case as a patient who was aged 0 to 18 years and identified by TCR during the period of October 1995 through September 2000 and enrolled by the HTI with clinically or culture-confirmed TB. We defined cases as clinically culture-confirmed when 2 of the following 3 criteria were met: (1) the patient’s clinical course was consistent with TB, (2) the tuberculin skin test (TST) was positive (⬎5 mm of induration), or (3) the patient clinically im-proved with treatment ofⱖ2 anti-TB drugs. We defined a case as culture confirmed when MTB was isolated from the patient’s clinical specimen.13Cases were also classified as pulmonary, ex-trapulmonary, or pulmonary-extrapulmonary TB on the basis of clinical presentation and/or laboratory results2:

1. Pulmonary TB: The lung was the site of disease, or MTB was isolated fromⱖ1 of the following specimens: sputum, gastric aspirate, bronchus, bronchial fluid, or lung.

2. Extrapulmonary TB: A site other than the lung was the site of disease, or MTB was isolated from a clinical specimen other than those listed above (eg, pleura, intrathoracic lymph nodes). 3. Pulmonary-extrapulmonary TB: The site of disease included

pulmonary and extrapulmonary sites.

A potential source case (PSC) was defined as an adult who had pulmonary TB and was identified by public health and/or HTI interviews as a close contact to a case patient. A close contact was defined as anyone who had close, regular, or prolonged contact with a case patient while he or she was infectious.14

Data Collection

After informed consent was obtained, case patients or their parents were interviewed using a standardized questionnaire. Evaluated risk factors and patient characteristics included demo-graphics, social contacts, economic status, travel history, living and social environment, medical history including TST status, family history, and exposure to TB. The same questionnaire was administered to PSCs. Using an interactive network of laboratory personnel, pediatric TB specialists, TCR workers, infection control officers, and HTI personnel, inpatient and outpatient records were reviewed as well as public health data to create a comprehensive medical history for each case patient and PSC.

Molecular Characterization

MTB isolates from case patients and PSCs were obtained, and a molecular profile for each isolate was created using 3 techniques; IS6110restriction fragment length polymorphism (RFLP), spoligo-typing, and genetic grouping. After extraction of mycobacterial

chromosomal DNA from isolates, IS6110 RFLP was performed using an internationally standardized protocol.15Each IS6110 pro-file was analyzed using BioImage Whole Band Analysis Program, version 3.2 (Ann Arbor, MI) and archived. Because IS6110RFLP cannot reliably differentiate isolates with 4 or fewer IS6110copies, spacer oligonucleotide typing (spoligotyping) was used to analyze MTB isolates further.16–20A commercially available kit was used for spoligotyping in accordance with the instructions supplied by the manufacturer (Bioscience BV, Maarssen, Netherlands). On the basis of the presence of nucleotide polymorphisms in codon 463 of thekatGgene encoding catalase-peroxidase and codon 95 of the

gyrAgene encoding the A subunit of DNA gyrase, isolates were analyzed to 1 of 3 major genetic groups.21When isolates had the same IS6110profile, spoligotype, and major genetic group, they were considered clonally related and grouped into the same clus-ter. In addition, we compared profiles to the HTI TB isolate database. Through 2002, the HTI had characterized 4342 isolates representing 3518 patients; 2166 (61.6%) isolates were grouped into 242 clusters, and 1352 (38.4%) were unique.

Data Analysis

Data from questionnaires were transcribed onto a stand-alone computer using EpiInfo 6.02b (Atlanta, GA) and Access (Mi-crosoft, Redmond, WA). Data analysis was performed using SAS 8.2 (SAS Institute Inc, Cary, NC).␹2analysis with odds ratio (OR) and 95% confidence interval (CI), Fisher’s exact test when the value of stratified age data were ⬍5, andt test were used for analysis of appropriate covariates.

RESULTS Demographics

During the period of October 1995 through Sep-tember 2000, 238 pediatric patients were identified by TCR and referred to HTI for enrollment in the study. On review by HTI staff, 18 pediatric patients were excluded because they were unable to be lo-cated (n⫽5), refused interview (n⫽3), or resided in Harris County⬍3 months before TB diagnoses (n⫽ 10). Thus, 220 (92%) pediatric TB patients who were identified during the study period were included in this study.

The mean age for case patients was 6.8⫾6.1 years, and the median age was 4 years. The proportion of enrolled male pediatric patients was slightly higher than that of female patients (Table 1). Although there were no statistical differences between the age dis-tribution of male and female patients in this study, patients who were aged 15 to 18 and presented with

TABLE 1. Demographics and Microbiology of Pediatric TB Cases by Age Group

Variables ⬍5 y,N(%) 5–14 y,N(%) 15–18 y,N(%) Total,N

Gender

Male 65 (58) 30 (27) 17 (15) 112

Female 53 (49) 29 (27) 26 (24) 108

Race

White 8 (67) 3 (25) 1 (8) 12

Black 47 (60) 25 (31) 7 (9) 79

Hispanic 59 (51) 28 (24) 29 (25) 116

Asian 4 (31) 3 (23) 6 (46) 13

Birth

US born 113 (61) 50 (27) 22 (12) 185

Foreign born 5 (14) 8 (26) 21 (60) 35

Culture

MTB isolated 41(52) 14 (18) 23 (29) 78

MTB not isolated 77 (54) 45 (32) 20 (14) 142

Molecular characterization*

Grouped into cluster 34 (66) 9 (18) 8 (16) 51

Not grouped into cluster 3 (15) 4 (20) 13 (65) 20

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TB were more likely to be female. The majority of case patients were ethnic minorities, with more than half being Hispanic. In addition, most case patients were born in the United States (n⫽185). Additional investigation of the US-born pediatric TB case pa-tients revealed that their parents were foreign born (n⫽56), US born (n⫽36), or unknown (n⫽93). The birth countries for foreign-born case patients were Mexico (n ⫽ 19), Latin American countries (n ⫽ 9), Vietnam (n⫽4), Cameroon (n⫽1), Nigeria (n⫽1), India (n ⫽ 1), and Columbia (n ⫽ 1). Eighty-five percent of US-born and foreign-born case patients had lived in Houston for ⬎1 year at the time of diagnosis.

Clinical Presentation

The majority of case patients were TST positive (n

⫽196), and most had an abnormal chest radiograph (n ⫽ 196). Examples of abnormal chest radiograph findings included adenopathy (n ⫽ 108), focal infil-trates (n⫽ 69), cavitary lesions (n⫽17), nodules (n

⫽ 14), or pleural effusions (n ⫽ 13). Of the 24 case patients with normal chest radiographs, 8 had cul-ture-confirmed TB: 3 with pulmonary TB diagnosed by sputum, lung biopsy, or gastric aspirate culture; 4 with extrapulmonary TB diagnosed by blood, lymph node, or hip joint culture; and 1 with pulmonary-extrapulmonary TB diagnosed by positive gastric as-pirate and cerebrospinal fluid (CSF) cultures.

For all enrollees, only 154 (70%) cultured cases were submitted for mycobacteriology evaluation, 78 (51%) of which had MTB isolated. The majority of cultures from which MTB was isolated were pulmo-nary sources, including sputum (n⫽25) and gastric aspirate (n⫽ 24); however, extrapulmonary sources were identified as well, including lymph node (n ⫽ 6), CSF (n ⫽ 2), pleural fluid (n ⫽ 2), bone (n ⫽ 1), blood (n⫽ 1), peritoneal fluid (n⫽1), joint (n⫽1), gastric lymph node (n⫽1), and omentum biopsy (n

⫽1). In several patients, MTB was isolated from⬎1 site, including sputum/gastric aspirate (n ⫽ 3), tis-sue biopsy/lung (n⫽2), bronchial wash/sputum (n

⫽1), CSF/gastric aspirate (n⫽4), CSF/gastric aspi-rate/urine (n⫽1), and ear/sputum (n⫽1). Of the 30 patients who were MTB culture positive from spu-tum specimens, 15 (50%) were acid-fast bacilli smear positive. The mean age of enrollees who submitted gastric aspirate–positive MTB cultures was 2.1⫾4.0 years and for enrollees who submitted sputum-pos-itive MTB cultures was 13.5⫾ 6.1 years. Only 7(9%) of the MTB isolates were resistant to at least 1 anti-mycobacterial drug, and multidrug-resistant TB was identified in 1 pediatric case.

On the basis of clinical and laboratory data, the site of disease for the majority of cases was extrapulmo-nary (n⫽111) followed by pulmonary (n⫽81) and

pulmonary-extrapulmonary (n ⫽ 28). Of the

ex-trapulmonary sites, the intrathoracic lymph nodes were the most commonly involved. Case patients who were agedⱖ5 years (OR: 1.80; 95% CI: 1.03–3.13; P ⫽ .04) as well as foreign-born case patients (OR: 3.13; 95% CI: 1.40 – 6.57;P⫽.002) were more likely to have pulmonary TB than case patients who were

younger than 5 years and US-born cases, respec-tively.

Molecular Characterization

We obtained MTB isolates from case patients and compared their molecular profiles with profiles of isolates that were obtained from PSCs. Of 33 case patients from whom PSC isolates were also available, the profiles matched in 30 (91%; Fig 1). In 3 cases (patients A, B, and C), the isolates did not match according to our cluster definition. Patient A was an otherwise healthy 3-year-old black, US-born boy who received a diagnosis of miliary TB. Patient A’s second cousin was identified as his PSC (PSC A). PSC A was a 41-year-old black man who had diabe-tes, mental illness, depression, and drug use and received a diagnosis of pulmonary TB 1 month be-fore patient A (Table 2). The molecular profiles for patient A and PSC A did not match but were similar with identical band patterns and genetic group. The spoligotype differed by 2 of 43 spacers (Table 3).

Patient B was an otherwise healthy 18-year-old Asian-Pacific boy who received a diagnosis of pul-monary TB. He reported drug use and exposure to jail and worked as a parking attendant. Patient B’s friend was identified as a PSC (PSC B). PSC B was a 54-year-old Asian-Pacific woman who was born in Vietnam and moved to the United States 3 years before patient B’s presentation, at which time she was TST positive (20 mm). One year after patient B’s presentation, MTB was isolated from PSC B’s spu-tum specimen. The molecular profiles from patient B and PSC B did not match as the band patterns were markedly different and the spoligotypes differed by 9 of 43 spacers (Table 3).

Patient C was an otherwise healthy 1-year-old black, US-born boy who received a diagnosis of pul-monary TB. Patient C’s grandfather was identified as his PSC (PSC C). PSC C was an otherwise healthy 35-year-old black man who received a diagnosis of pulmonary TB 2 months before patient C. PSC was born in the United States, reported drug use 20 years before TB diagnosis, and was incarcerated 8 years

220cases

143 with potential source case

109 with verified* potential source case

Profile from case compared to profile from potential source case

30 with profiles that matched potential source case profiles

33 with isolate available from verified potential source case for profiling 36 with isolate available for characterization

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before diagnosis. The molecular profiles of patient C and PSC C did not match but were similar, differing by only 1 band and belonging to the same genetic group (Table 3).

MTB isolates from case patients with no known source case were evaluated to determine whether PSCs could be identified using molecular techniques (Fig 2). After comparing isolates with the HTI TB isolate database, we identified 4 PSCs. Additional evaluation of these cases (patients D, E, F, and G) revealed that patient D was an otherwise healthy Hispanic 1-year-old girl who had a diagnosis of pul-monary TB. Patient D was born in the United States; however, during the 6 months before her diagnosis, she was exposed to multiple adults who moved from Honduras during the previous 5 years. Molecular characterization identified patient D’s aunt as a PSC (PSC D). PSC D was an otherwise healthy 26-year-old Hispanic woman who received a diagnosis of pulmonary TB⬃1 year after patient D.

Patient E was an otherwise healthy 14-year-old Hispanic boy who received a diagnosis of pulmo-nary TB. Patient E had no history of exposure to jail or long-term care facilities, was born in the United

States, and reported having traveled to Mexico to visit relatives 1 time during the 6 months before his diagnosis. Molecular characterization identified an unrelated adult with no known epidemiologic link to patient E as a PSC (PSC E). PSC E was a previously healthy 44-year-old Hispanic woman who received a diagnosis of pulmonary TB 9 months before patient E. PSC E was born in the United States and had no jail or long-term care facilities exposure.

Patient F was otherwise healthy 16-year-old His-panic girl who received a diagnosis of pulmonary TB. Patient F was born in the United States and reported no exposure to jail or long-term facilities. Molecular characterization identified an unrelated adult with no epidemiologic link to patient F as a PSC (PSC F). PSC F received a diagnosis of TB 4 years before patient F, and only limited clinical informa-tion was available for this 35-year-old white man.

Patient G was an otherwise healthy 7-year-old His-panic girl who received a diagnosis of MTB osteo-myelitis of her left femoral head. Patient G was born in El Salvador and had visited her brother while he was in jail. Molecular characterization identified an unrelated adult with no known epidemiologic link to patient G as a PSC (PSC G). PSC G was an 82-year-old Asian Pacific man who received a diagnosis of pulmonary TB 2 years after patient G. PSC G was born in China and was enlisted in the military from 1940 to 1950. He moved to the United States 20 years before TB presentation and then to Houston after 10 years.

We received MTB cultures from 73 (93.5%) of the 78 culture-positive cases. We were able to perform molecular characterization on 71 (97.3%) of the 73 MTB isolates. Fifty-one (71.8%) MTB isolates matched at least 1 other isolate within the HTI TB isolate database and were grouped into 33 molecular

220cases

77 with unknown potential source case

25 with isolate available for characterization

Profile from case compared to HTI TB database

4 with profile that matched profile from HTI TB database

Fig 2. Pediatric TB case patients with PSCs identified with molec-ular characterization: Harris County, 1995–2000.

TABLE 2. Summary of Epidemiologic and Clinical Data for Case Patients and PSCs

Age, y Race Gender Birth Medical/Social TB Disease Method of

Identifying PSC

PSC

3 Black Male US Miliary Contact Investigation PSC A

18 Asian Pacific Male US Jail, drug use Pulmonary Contact investigation PSC B

1 Black Male US Exposure to incarcerated

adults

Pulmonary Contact investigation PSC C

1 Hispanic Female US Exposure to adults from Honduras

Pulmonary HTI TBD PSC D

14 Hispanic Male US Travel to Mexico Pulmonary HTI TBD PSC E

16 Hispanic Female US Pulmonary HTI TBD PSC F

7 Hispanic Female Foreign Exposure to incarcerated adult

Femur HTI TBD PSC G

TBD indicates TB Isolate Database.

TABLE 3. Summary of the Molecular Characterization Including IS6110RFLP, Genetic Group, and Spoligotyping for Case Patients Whose Molecular Characterization Did Not Match Identified PSCs’ Molecular Characterization: Houston, 1995–2000

Case Patient Copy* Genetic Group† Spoligotyping PSC Copy Genetic Group Spoligotyping

A 2 2 52 A 2 2 12

B 12 1 180 B 1 1 10

C 14 1 1 C 13 1 ‡

* Number of IS6110RFLP bands. † Defined per Sreevatsan et al.20

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clusters. Case patients who were younger than 5 years were more likely to be clustered than those who wereⱖ5 years of age (OR: 17.98; 95% CI: 3.6 – 84.6;P⬍.001). Case patients who identified a source case (OR: 3.73; 95% CI: 1.25–11.19; P ⫽ 0.02) were more likely to be clustered than those who did not identify a source case. In addition, case patients who were born in the United States (OR: 6.90; 95% CI: 2.00 –23.82;P⫽ ⬍0.001) were more likely to be clus-tered than foreign-born case patients. Using methods outlined by Sreevatsan et al,20 we divided case iso-lates into major genetic groups. Most isoiso-lates were classified in major genetic group 2 (n⫽36), followed by major genetic group 1 (n⫽25) and major genetic group 3 (n ⫽ 10). On the basis of the molecular profiles and characteristic spoligotype pattern, 20 (28.2%) of the 71 isolates belong to the Beijing family strains.22Eighteen (90%) of the 20 isolates that were Beijing family strains were clustered.

DISCUSSION

We analyzed the clinical factors in combination with molecular profiling to characterize further the TB transmission among pediatric patients in Hous-ton, Texas. Although molecular techniques have been used to describe TB transmission in a number of settings, few studies involved a pediatric popula-tion.5,11,23The majority of our cases occurred in chil-dren who were younger than 5 years and among ethnic minorities. It is interesting that the ethnic dis-tribution of case patients did not reflect the general population. In 2001, 32.9% of the general population of Houston was Hispanic, whereas in our study, 52.7% of the case patients were Hispanic. Hispanic children and young adults are known to have a higher incidence of disease and may be related to several factors, including recent immigration, socio-economic status, high-risk behavior, and possibly genetic susceptibility.24 In addition, the Mexican states that border the United States, particularly those that border Texas, have higher rates of TB.25

Although the majority of case patients were TST positive with abnormal chest radiographs, 17 (7.7%) were TST negative and 21 (9.6%) had normal chest radiographs. In addition, 76 (49%) had negative cul-tures. Our results are consistent with previous re-ports of TST and culture sensitivity in children and serve as a reminder that pediatric TB may be clini-cally silent and difficult to diagnose.26 Rates of

ex-trapulmonary disease, however, were higher in our study as compared with national data.27 Possible explanations include an overall trend toward younger age at diagnosis in Houston. Between 1996 and 2000, the mean age of pediatric TB patients in Houston declined, and this may have had an impact on disease presentation. Another explanation is that cases were diagnosed earlier. If, for example, most cases were evaluated as part of a contact investiga-tion rather than because of symptomatic disease, then they may not have had time to progress from hilar adenopathy, which was defined as extrapulmo-nary to pulmoextrapulmo-nary disease.

Molecular characterization helped to verify source case information. Although the majority of case iso-lates matched their source case isoiso-lates, 3 did not. Additional evaluation of isolates revealed that in 2 cases (patients A and C), the isolates from case pa-tients and PSCs were similar. It is interesting that for both patients A and C, the PSCs were family mem-bers; thus, the nonmatching profiles may have re-flected our strict definition matching rather than a misidentified PSC. Also, the slight change in molec-ular profile between case patient and PSC suggests the possibility of a change in molecular profile with transmission.20In contrast, the isolate from patient B and from PSC B had truly different molecular pro-files with different drug susceptibility patterns; pa-tient B was drug resistant, and the PSC B was drug susceptible. Our results suggest that for certain pe-diatric patients, therapy that is based on adult source case culture data cannot be assumed, as transmission of multidrug-resistant TB may have occurred through an unknown contact.28,29In addition, molec-ular characterization helped to identify 4 previously unrecognized PSCs. Although an epidemiologic link was found in 1 of the 4 cases (patient D), transmis-sion that is based on molecular characterization is controversial and ignores the possibility of addi-tional exposures such as through travel. It is inter-esting that patient E’s cluster included isolates that were obtained from family members, but because they were diagnosed after patient E, they were not identified as a PSC. Thus, molecular characterization did not identify the most likely PSC, but it did high-light the role that asymptomatic adults play in TB transmission to children.

The majority of cases from whom molecular char-acterization was available were grouped into clus-Relationship to

Case Patient

Age, y Race Gender Birth Medical/Social Disease Comparison of

Molecular Profiles

Cousin 41 Black Male US Diabetes, depression,

drug use

Pulmonary Nonmatching

Friend 54 Asian Pacific Female Foreign Pulmonary Nonmatching

Grandfather 35 Black Male US Drug use, jail Pulmonary Nonmatching

Aunt 26 Hispanic Female Foreign Moved to US 2 y

before

Pulmonary Matching

None 44 Hispanic Female US Pulmonary Matching

None 35 White Male Matching

None 82 Asian Pacific Male Foreign Enlisted in military

in China

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ters, suggesting that recent transmission played a significant role in our population. Risk factors for clustering included age⬍5 years, having an identi-fied source case, and being born in the United States. Similar trends have been found in the adult popula-tion, in which higher clustering rates among US-born case patients has been documented.5,11,30–33Reasons for foreign-born case patients’ having lower rates of clustering may be different in adults and children. Foreign-born adults are more likely to have reacti-vated disease acquired before immigration, reflect-ing the epidemiology of their country of origin. In contrast, children are more likely to progress from infection to disease and mirror the epidemiology of their source case.

Spoligotyping has been shown to correlate well with major genetic group designations and can help to differentiate between clones. In our study, the majority of MTB isolates belonged to major genetic group 2. Soini et al34 found a similar distribution of the genetic groups among adult TB cases in Houston. We identified one case of Mycobacterium bovisusing spoligotyping, whereas Dankner et al35 found that 33.9% of cases were M bovis. A difference in unpas-teurized milk consumption, a known risk factor for M bovisinfection, may explain the difference in fre-quency of M bovis. Whether the patient who had a case ofM bovisin our study consumed unpasteurized milk is unknown.

Twenty-eight percent of the isolates in our study belonged to the Beijing family based on spoligotype patterns. This strain has been associated with out-breaks of TB and drug resistance in several parts of the world. Soini et al34found a similar trend among adults in Houston, where 25% were found to have patterns consistent with the Beijing family. These findings support other studies in which an associa-tion between age and Beijing strain isolaassocia-tion has not been established.36–38 It is interesting that90% of the Beijing strains were clustered, suggesting that recent transmission may also play a role among Bei-jing strains that are isolated from children.

An important limitation to this study is the differ-ences in case presentation. Whether a case was re-ferred to TCR for evaluation because of school pol-icy, a positive TST, as part of contact investigation, or as a result of symptoms consistent with TB may have had an impact on both the severity of disease at presentation and, consequently, the initial work-up (ie, decision to obtain chest x-ray or cultures). In addition, cultures were not obtained from all pa-tients; thus, the degree of clustering may have been underestimated. The decision to collect cultures was made on an individual basis by pediatricians and dependent on whether cultures were available from a source case. Cultures were less likely to be obtained from a patient when a PSC had been identified, as pediatric TB clinicians often rely on the culture and the sensitivity results from the PSC in treatment de-cisions for the child. Only 2 investigators performed the majority of clinical evaluations, so the degree of variability in case evaluation may have been inher-ently limited. In addition, most of the data analysis was presented in aggregate. Thus, the ability to make

conclusions about risk factors for TB exposure may be limited, as many risk factors for TB exposure are age dependent. Finally, usefulness of DNA finger-printing in pediatric TB is limited as children are often culture negative. In our study, only 154 (70%) patients had cultures obtained, of which only 78 (51%) had MTB isolated. Thus, MTB was isolated from only 78 (35%) of 220 patients.

CONCLUSIONS

This is the first study to evaluate the population-based epidemiology of pediatric TB using molecular techniques. Our data suggest that traditional contact tracing may not be accurate and that molecular char-acterization can serve as an additional tool to verify and identify PSCs. In addition, molecular profiling should be used to assess the burden of TB disease as a result of recent transmission through the identifi-cation of clusters. Communities with evidence of recent transmission, such as children who are younger than 5 years, are important targets for TB control programs.

For clinicians, acquiring a culture in a pediatric patient should be a high priority. In addition, iden-tifying adult contacts by all available methods, in-cluding molecular characterization as recently rec-ommended by the Centers for Disease Control and Prevention, should be attempted to identify correctly source cases and to determine correct susceptibility profile so that appropriate therapy can be initiated.39 Emphasis on these strategies will give a more com-plete picture of both pediatric and overall TB trans-mission in the community.

ACKNOWLEDGMENTS

This project was funded in part with the federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, under contract N01-A0-02738 and AI 41168.

We acknowledge the following members of the Houston Tu-berculosis Initiative: Natalie Williams-Bouyer, Xi Pan, Conception Cantu, Heather Tooker-Blue, Thanh Tung Bui, and Syed N. Khalil.

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AIRLINE CHILD SAFETY SEATS

“The Federal Aviation Administration has decided against a proposal to require the use of child safety seats aboard airline flights—a move that would have forced parents to buy tickets for small children who otherwise could sit in parents’ laps. In a statement released by the F.A.A. late last month, Marion C. Blakey, a spokes-woman for the agency, cited safety as the primary concern. ‘Statistics show that families are safer traveling in the sky than on the road,’ she said. ‘If requiring extra airline tickets forces some families to drive, then we’re inadvertently putting too many families at risk.’ ”

Considine A.New York Times. September 11, 2005

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DOI: 10.1542/peds.2004-2701

2005;116;1141

Pediatrics

Connelly Smith, James M. Musser, Jeffrey R. Starke and Edward A. Graviss

Susan H. Wootton, Blanca E. Gonzalez, Rebecca Pawlak, Larry D. Teeter, Kim

Techniques: Houston, Texas

Epidemiology of Pediatric Tuberculosis Using Traditional and Molecular

Services

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http://pediatrics.aappublications.org/content/116/5/1141

including high resolution figures, can be found at:

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DOI: 10.1542/peds.2004-2701

2005;116;1141

Pediatrics

Connelly Smith, James M. Musser, Jeffrey R. Starke and Edward A. Graviss

Susan H. Wootton, Blanca E. Gonzalez, Rebecca Pawlak, Larry D. Teeter, Kim

Techniques: Houston, Texas

Epidemiology of Pediatric Tuberculosis Using Traditional and Molecular

http://pediatrics.aappublications.org/content/116/5/1141

located on the World Wide Web at:

The online version of this article, along with updated information and services, is

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Figure

TABLE 1.Demographics and Microbiology of Pediatric TB Cases by Age Group
Fig 1. Pediatric TB case patients with PSCs verified with molec-ular characterization: Harris County, 1995–2000
TABLE 2.Summary of Epidemiologic and Clinical Data for Case Patients and PSCs

References

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