Robert P. Gie

Exogenous Reinfection as a Cause of Recurrent Tuberculosis after Curative Treatment

BACKGROUND For decades it has been assumed that postprimary tuberculosis is usually caused by reactivation of endogenous infection rather than by a new, exogenous infection. METHODS We performed DNA fingerprinting with restriction-fragment-length polymorphism analysis on pairs of isolates of Mycobacterium tuberculosis from 16 compliant patients who had a relapse of pulmonary tuberculosis after curative treatment of postprimary tuberculosis. The patients lived in areas of South Africa where tuberculosis is endemic. Medical records were reviewed for clinical data. RESULTS For 12 of the 16 patients, the restriction-fragment-length polymorphism banding patterns for the isolates obtained after the relapse were different from those for the isolates from the initial tuberculous disease. This finding indicates that reinfection was the cause of the recurrence of tuberculosis after curative treatment. Two patients had reinfections with a multidrug-resistant strain. All 15 patients who were tested for the human immunodeficiency virus were seronegative. CONCLUSIONS Exogenous reinfection appears to be a major cause of postprimary tuberculosis after a previous cure in an area with a high incidence of this disease. This finding emphasizes the importance of achieving cures and of preventing anyone with infectious tuberculosis from exposing others to the disease.

Bacille Calmette-Guérin Vaccine—Induced Disease in HIV-Infected and HIV-Uninfected Children

Bacille Calmette-Guerin (BCG)--a live attenuated vaccine--is routinely given to neonates in settings where tuberculosis is endemic irrespective of human immunodeficiency virus (HIV) exposure. HIV infected infants and other immunodeficient infants are at risk of BCG-related complications. We report the presentation treatment and mortality of children who develop BCG disease with emphasis on HIV-infected children. In addition we present a revised classification of BCG disease in children and propose standard diagnostic and management guidelines. This retrospective hospital-based study was conducted in the Western Cape Province South Africa. Mycobacterium tuberculosis complex isolates recovered from children aged < 13 years during the period of August 2002 through January 2005 were speciated by polymerase chain reaction to confirm Mycobacterium bovis BCG. Clinical data were collected through medical file review. BCG disease was classified according to standard and revised disease classifications. Mortality was assessed at the end of the study period. BCG disease was diagnosed in 25 children; 22 (88%) had local disease and 8 (32%) had distant or disseminated disease; 5 children (20%) had both local and distant or disseminated disease. Seventeen children were HIV infected; 2 children had other immunodeficiencies. All 8 children with distant or disseminated disease were immunodeficient; 6 were HIV infected. The mortality rate was 75% for children with distant or disseminated disease. BCG vaccination poses a risk to infants perinatally infected with HIV and to other primary immunodeficient children. The proposed pediatric BCG disease classification reflects clinically relevant disease categories in HIV-infected children. The suggested diagnostic and treatment guidelines should improve existing case management and surveillance. Prospective evaluation of management strategies for BCG disease in HIV infected and HIV-uninfected children is essential. (authors)

Evaluation of Tuberculosis Diagnostics in Children: 1. Proposed Clinical Case Definitions for Classification of Intrathoracic Tuberculosis Disease. Consensus From an Expert Panel

There is a critical need for improved diagnosis of tuberculosis in children, particularly in young children with intrathoracic disease as this represents the most common type of tuberculosis in children and the greatest diagnostic challenge. There is also a need for standardized clinical case definitions for the evaluation of diagnostics in prospective clinical research studies that include children in whom tuberculosis is suspected but not confirmed by culture of Mycobacterium tuberculosis. A panel representing a wide range of expertise and child tuberculosis research experience aimed to develop standardized clinical research case definitions for intrathoracic tuberculosis in children to enable harmonized evaluation of new tuberculosis diagnostic technologies in pediatric populations. Draft definitions and statements were proposed and circulated widely for feedback. An expert panel then considered each of the proposed definitions and statements relating to clinical definitions. Formal group consensus rules were established and consensus was reached for each statement. The definitions presented in this article are intended for use in clinical research to evaluate diagnostic assays and not for individual patient diagnosis or treatment decisions. A complementary article addresses methodological issues to consider for research of diagnostics in children with suspected tuberculosis.

Analysis for a Limited Number of Gene Codons Can Predict Drug Resistance of Mycobacterium tuberculosis in a High-Incidence Community

ABSTRACT Correct and rapid diagnosis is essential in the management of multidrug-resistant tuberculosis (MDR-TB). In this population-based study of 61 patients with drug-resistant tuberculosis, we evaluated the frequency of mutations and compared the performance of genotypic (mutation analysis by dot blot hybridization) and phenotypic (indirect proportion method) drug resistance tests. Three selected codons (rpoB531, rpoB526, and katG315) allowed identification of 90% of MDR-TB cases. Ninety percent of rifampin, streptomycin, and ethambutol resistance and 75% of isoniazid resistance were detected by screening for six codons: rpoB531, rpoB526, rrs-513, rpsL43, embB306, and katG315. The performance (reproducibility, sensitivity, and specificity) of the genotypic method was superior to that of the routine phenotypic method, with the exception of sensitivity for isoniazid resistance. A commercialized molecular genetic test for a limited number of target loci might be a good alternative for a drug resistance screening test in the context of an MDR “DOTS-plus” strategy.

Respiratory tuberculosis in childhood: the diagnostic value of clinical features and special investigations.

During a 16-month period children presenting to a pediatric outpatient facility from an area with a high tuberculosis incidence (> 400/100 000) and suspected of having respiratory tuberculosis (TB) were evaluated for close contact with adult pulmonary tuberculosis, weight loss, symptom duration, respiratory signs, lymphadenopathy and hepatosplenomegaly and by chest radiography and tuberculin testing (Mantoux or tine). Probable tuberculosis was diagnosed in 258 children and was confirmed in 109 (42%) patients with a mean age of 31 months by culture of Mycobacterium tuberculosis from gastric aspirate or another source. Eleven children with confirmed TB had a normal chest radiograph. After review of special investigations, clinical course and follow-up of the remaining 149 children, 86 children (58%) with a mean age of 32.4 months were considered to have probable TB and 63 (42%) with a mean age of 27 months not to have TB. Significantly fewer children in the “not TB” group than in the confirmed and probable TB groups had a close adult pulmonary tuberculosis contact (13 (21%) and 95 (49%), respectively; P < 0.01). There was no difference between the “not TB” group and the confirmed and probable TB groups in the proportion presenting with weight loss, cough or other respiratory symptoms, a symptom duration >2 weeks, the presence of bronchial breathing, wheeze, hepatomegaly or splenomegaly or peripheral lymphadenopathy. Final diagnoses in the “not TB” group included bacterial or viral pneumonia or bron-chopneumonia in 37, asthma often accompanied by segmental collapse in 9 and cavitating pneumonia in 3 children. On the one hand children in whom there were sufficient criteria to be considered probable cases of TB were subsequently thought not to have TB; on the other hand 11 (10%) of children with TB confirmed by culture of Mycobacterium tuberculosis from gastric aspirate had a normal chest radiograph.

Childhood tuberculosis in an urban population in South Africa:burden and risk factor

AIM To study the epidemiology of childhood tuberculosis (TB) in a developing country. SETTING Two urban communities of Cape Town, South Africa with a TB case notification rate of 1149/100 000. DESIGN Retrospective descriptive study using the national population census (1991), 10 year official TB notification records, and a geographical information system. RESULTS The case notification rate of TB in children 0–5 years old was 3588 cases/100 000 children aged 0–5 years, 3.5 times the case notification rate in adults. Children (0–14 years) accounted for 39% of the total case load. Childhood TB case notification rate correlated with parental education (r = −0.64), annual household income (r = −0.6), and crowding (r = 0.32). CONCLUSION Children, especially those living in poor socioeconomic conditions, form an important epidemiological group and account for a notable proportion of the morbidity caused by TB. Efforts to improve TB control must therefore not only target adults (case detection and cure of infectious cases) but also children (screening of child contacts of adult cases) and the socioeconomic living conditions.

Transmission of a Multidrug-Resistant Mycobacterium tuberculosis Strain Resembling “Strain W” among Noninstitutionalized, Human Immunodeficiency Virus—Seronegative Patients

Since 1990, several outbreaks of multidrug-resistant tuberculosis (MDR-TB) have been described among institutionalized patients infected with human immunodeficiency virus (HIV). We describe a community MDR-TB outbreak among HIV-seronegative patients in Cape Town, South Africa. Isolates were characterized by restriction fragment length polymorphism (RFLP) analysis and dot-blot hybridization analysis of mutations conferring resistance for isoniazid, rifampin, streptomycin, and ethambutol. All isolates were identical on RFLP analysis. In 2 patients, RFLP analysis showed exogenous reinfection during or after treatment for drug-susceptible TB. Mutation analysis confirmed the genotypic identity of the isolates. The infecting strain was genotypically related to strain W, which is responsible for the majority of MDR-TB outbreaks in New York City. Transmission of MDR-TB is thus not limited to HIV-seropositive patients in an institutional setting but occurs within a community.

Danish Bacille Calmette-Guérin Vaccine-Induced Disease in Human Immunodeficiency Virus-Infected Children

An analysis of isolates of Mycobacterium tuberculosis complex was performed to determine the prevalence of bacille Calmette-Guérin (BCG) disease among human immunodeficiency virus (HIV)-infected children. Speciation was done with polymerase chain reaction; 183 isolates from mycobacterial cultures for 49 HIV-infected patients were analyzed. The Danish Mycobacterium bovis BCG strain was isolated from 5 patients. No cases of Tokyo M. bovis BCG strain disease were detected. All patients were asymptomatic at birth, <12 months of age, and severely immunodeficient at presentation. Four patients had regional axillary adenitis ipsilateral to the vaccination site, and 2 had pulmonary BCG disease. Two patients with regional BCG disease had simultaneous pulmonary M. tuberculosis infection. Although chest radiographic features were similar to those seen in patients with tuberculosis, BCG disease should be considered in HIV-infected infants with right axillary adenitis ipsilateral to the vaccination site. Young, symptomatic, HIV-infected infants are at risk for BCG-related complications. Controlled, population-based studies are needed to assess the risk of BCG in HIV-infected children.

Impact of social interactions in the community on the transmission of tuberculosis in a high incidence area

BACKGROUND Tuberculosis (TB) is transmitted by close contact with an infectious person. It is assumed that close contact occurs amongst household members and that contact outside the house is “casual” and does not play a major role in the transmission of TB. METHODS This study was conducted in an impoverished area with a high incidence of TB and a low HIV seropositive prevalence. Thirty three households with 84 TB patients were identified between February 1993 and April 1996 and the transmission of TB was studied by combiningMycobacterium tuberculosis fingerprinting with in depth sociological interviews. RESULTS Forty two strain genotypes were identified in the 84 patients. In 15 households all the patients had identical strains, in nine households all the patients had different strains, and in nine households some patients had identical strains and one had a different strain. In 26 houses at least one patient had a strain which formed part of a larger community cluster and in 12 of these households the patient(s) had contact with a community member who had the identical strain. In 58% of the cases the contact took place while drinking in social groups. CONCLUSION In high incidence areas contact outside the household may be important for the transmission of TB. This contact often takes place during recreation which, in the case of this study of impoverished people, consisted of drinking in social groups. Social interaction patterns should be studied and understood for effective implementation of control strategies.

Multiple Mycobacterium tuberculosis Strains in Early Cultures from Patients in a High-Incidence Community Setting

ABSTRACT In an ongoing molecular epidemiology study, human immunodeficiency virus-negative patients with first-time pulmonary tuberculosis from a high-incidence community were enrolled. Mycobacterium tuberculosis strains were identified by restriction fragment length polymorphism analysis with two fingerprinting probes. Of 131 patients, 3 (2.3%) were shown to have a mixture of strains in one or two of their serial cultures. This study further investigated these cases with disease caused by multiple M. tuberculosis strains in the context of the molecular epidemiology of the study setting.