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P M Small

Publications and source records attributed to P M Small.

At least 37 records · Page 2Linked to original sources
PubMed2000

Tuberculosis in the homeless. A prospective study.

We set out to determine tuberculosis incidence and risk factors in the homeless population in San Francisco. We also examined the transmission of tuberculosis by molecular methods. We followed a cohort of 2,774 of the homeless first seen between 1990 and 1994. There were 25 incident cases during the period 1992 to 1996, or 270 per 100,000 per year (350/100,000 in African Americans, 450/100,000 in other nonwhites, 60/100,000 in whites). Ten cases were persons with seropositive HIV. Independent risk factors for tuberculosis were HIV infection, African American or other nonwhite ethnicity, positive tuberculin skin test (TST) results, age, and education; 60% of the cases had clustered patterns of restriction fragment length polymorphism, thought to represent recent transmission of infection with rapid progression to disease. Seventy-seven percent of African-American cases were clustered, and 88% of HIV-seropositive cases. The high rate of tuberculosis in the homeless was due to recent transmission in those HIV-positive and nonwhite. African Americans and other nonwhites may be at high risk for infection or rapid progression. Control measures in the homeless should include directly observed therapy and incentive approaches, treatment of latent tuberculous infection in those HIV-seropositive, and screening in hotels and shelters.

Adult↗
PubMed2000

The role of core groups in transmitting Mycobacterium tuberculosis in a high prevalence community in Southern Mexico.

SETTING: A community in Southern Mexico with a high prevalence of tuberculosis. OBJECTIVE: To characterize the transmission dynamics in a region with a DOTS-based tuberculosis control program. DESIGN: Community-based screening of chronic coughers between 1 March 1995 and 31 August 1996. Individuals with acid-fast bacilli (AFB) in their sputum were enrolled, interviewed, and had mycobacterial cultures and fingerprinting performed. In-depth interviews were conducted on all persons with DNA fingerprinting. RESULTS: AFB smears were performed on 1424 individuals, 124 of whom were microbiologically confirmed. Of the 95 cases for whom bacterial DNA fingerprints were available, 38 were in clusters. The largest cluster involved seven individuals who were members of a social network centered on a series of unlicensed bars. CONCLUSION: This population-based molecular epidemiologic study showed that a focus of transmission within a social network accounted for one fourth of transmission which rapidly progressed to disease. These observations raise questions about the potential benefit of targeted tuberculosis control interventions in health jurisdictions approaching WHO-defined DOTS benchmarks.

Cluster Analysis↗
PubMed2000

Sex differences in the epidemiology of tuberculosis in San Francisco.

SETTING: Worldwide differences in sex-specific tuberculosis case rates remain fundamentally unexplained. OBJECTIVE: To explore various factors that may explain sex differences in tuberculosis incidence rates for San Francisco from 1991-1996. DESIGN: A retrospective epidemiologic analysis of sex-specific tuberculosis incidence rates in San Francisco from 1991-1996. Stratified analyses were performed on age at diagnosis, racial/ethnic group, human immunodeficiency virus (HIV) status, and place of birth. Molecular fingerprinting with IS6110 data was used to study sex differences in the incidence of disease for recently transmitted and reactivated cases of tuberculosis. RESULTS: In the study period, the male to female incidence rate ratio was 2.1 (95% CI 1.9-2.3). Stratified analyses revealed differences in sex-specific rates after the age of 14 and the highest male:female ratios were seen in the US-born, white, and black populations. High ratios were also observed for cases with clustered fingerprints, similar to those observed for the US-born population. In sub-populations with predominantly reactivated cases of tuberculosis, ratios were also above unity after adolescence, but the effect was less pronounced. CONCLUSION: The ongoing transmission of tuberculosis in the US-born population is one of the factors that explains the difference in sex-specific rates of disease in San Francisco. Observed differences in tuberculosis rates between the sexes may be due to a difference in transmission dynamics rather than diagnosis or reporting biases.

AIDS-Related Opportunistic Infections↗
PubMed2000

Transmission of tuberculosis in San Francisco and its association with immigration and ethnicity.

OBJECTIVE: To determine tuberculosis transmission dynamics in San Francisco and its association with country of birth and ethnicity. METHODS: Restriction fragment length polymorphism (RFLP) typing was performed on Mycobacterium tuberculosis isolates from culture-positive pulmonary tuberculosis patients in San Francisco (1991 through 1996), using IS6110 as a probe. Patients were assigned to clusters based on mycobacterial isolates with identical DNA fingerprints. Clusters were assumed to have arisen from recent transmission. A transmission index was defined as the average number of culture-positive pulmonary tuberculosis cases generated by a single source case and calculated for subgroups. RESULTS: The transmission index was higher in US-born (0.59) than in foreign-born groups (0.21), and was highest in blacks, in particular those aged under 35 years. The increased transmission index among blacks was not explained by smear-positivity, human immunodeficiency virus infection, or increased susceptibility to disease progression. CONCLUSION: US-born tuberculosis cases generated more secondary cases than immigrants. Young blacks appear to be a high-risk group for tuberculosis transmission. These results suggest the need to develop interventions targeted towards this risk group.

Adolescent↗
PubMed2000

Pattern recognition of genomic features with microarrays: site typing of Mycobacterium tuberculosis strains.

Mycobacterium tuberculosis (M. tb.) strains differ in the number and locations of a transposon-like insertion sequence known as IS6110. Accurate detection of this sequence can be used as a fingerprint for individual strains, but can be difficult because of noisy data. In this paper, we propose a non-parametric discriminant analysis method for predicting the locations of the IS6110 sequence from microarray data. Polymerase chain reaction extension products generated from primers specific for the insertion sequence are hybridized to a microarray containing targets corresponding to each open reading frame in M. tb. To test for insertion sites, we use microarray intensity values extracted from small windows of contiguous open reading frames. Rank-transformation of spot intensities and first-order differences in local windows provide enough information to reliably determine the presence of an insertion sequence. The nonparametric approach outperforms all other methods tested in this study.

Genome, Bacterial↗
PubMed2000

Use of multiple markers in population-based molecular epidemiologic studies of tuberculosis.

SETTING: Many epidemiologic studies of tuberculosis are being conducted worldwide. Fingerprinting with a secondary marker in strains with fewer than six IS6110-hybridizing bands enhances the tracking of strains, but its impact on population-level inferences has not been well studied. OBJECTIVE: To investigate the effects of secondary genotyping for low-copy Mycobacterium tuberculosis isolates with polymorphic guanine-cytosine-rich repetitive sequence (PGRS) on epidemiologic inferences in population-based research settings. DESIGN: For San Francisco tuberculosis cases (1991-1996), clusters were defined by IS6110 alone and by PGRS/IS6110 to 1) estimate recent transmission, 2) evaluate the theoretical influence of bacterial population parameters on these estimates, and 3) assess risk factors for recent transmission. RESULTS: Secondary typing on low-copy strains (20.3% of all isolates) decreased the estimate of recent transmission from 29.1% to 25.3% (P = 0.03). The most influential parameters in determining whether supplemental genotyping results in different estimates were the proportion of low-copy strains and the amount of clustering. Risk factors for recent transmission were identical for both definitions of clustering. CONCLUSION: The statistical and inferred effects of secondary genotyping of M. tuberculosis seem to depend on the proportion of low-copy strains in the population. When this proportion is low or when few secondary patterns match, supplemental genotyping may yield minimal insight into population-level investigations.

Adult↗
PubMed2000

Mycobacterium tuberculosis drug resistance in a suburban community in southern Mexico.

OBJECTIVE: To determine the impact of drug resistance (DR) on the clinical outcome and transmission of tuberculosis under programmatic conditions. METHODS: Prospective cohort and molecular epidemiologic study in the Orizaba Health Jurisdiction of Mexico. Between March 1995 and July 1999, chronic coughers with positive acid-fast bacilli (AFB) detected in sputum smear underwent clinical and mycobacteriologic evaluation (species identification, drug susceptibility testing and IS6110-based genotyping). Treatment was provided in accordance with official norms. RESULTS: Mycobacterium tuberculosis was isolated from 326/387 AFB-positive cases. The rate of DR was 24.2% and that of multidrug resistance (MDR, defined as resistance to both isoniazid and rifampin at least) was 7.7%; 78% were cured, 8% abandoned treatment, 6% failed treatment, and 5% died. An additional 13.5% received retreatment and 8.9% died during a median 28.6 months of follow up. Factors associated with DR by multivariate analysis were chronicity of tuberculosis (OR 4.8, 95%CI 2.7-8.4, P < 0.001), age >40 years (OR 1.9, 95%CI 1.1-3.2, P = 0.02) and indigenous origin (OR 0.3, 95%CI 0.13-0.75, P = 0.01). Cox-adjusted relative risks showed that MDR (RR 2.5, 95%CI 1.02-6.16, P = 0.04), HIV infection (RR 31.3, 95%CI 11.6-84.8, P < 0.001), and chronicity of tuberculosis (RR 2.1, 95%CI 1.0-4.4, P = 0.06) were associated with mortality, controlling for age. Predictors of retreatment were DR (not including MDR) (RR 2.2 95%CI 0.89-5.31, P < 0.087), MDR (RR 12.6, 95%CI 5.46-28.88, P < 0.001), and living in a household with an earthen floor (RR 2.8, 95%CI 1.27-6.13, P = 0.011). Being infected with MDR-TB was the only factor associated with a decreased likelihood of being in an RFLP cluster (OR 0.31, 95%CI 0.12-0.81, P = 0.02). CONCLUSIONS: Although MDR-TB may have a decreased propensity to spread and cause disease, it has a profoundly negative impact on tuberculosis control.

Adult↗
PubMed1999

A molecular epidemiologic analysis of tuberculosis trends in San Francisco, 1991-1997.

BACKGROUND: To decrease tuberculosis case rates and cases due to recent infection (clustered cases) in San Francisco, California, tuberculosis control measures were intensified beginning in 1991 by focusing on prevention of Mycobacterium tuberculosis transmission and on the use of preventive therapy. OBJECTIVE: To describe trends in rates of tuberculosis cases and clustered cases in San Francisco from 1991 through 1997. DESIGN: Population-based study. SETTING: San Francisco, California. PATIENTS: Persons with tuberculosis diagnosed between 1 January 1991 and 31 December 1997. MEASUREMENTS: DNA fingerprinting was performed. During sequential 1-year intervals, changes in annual case rates per 100,000 persons for all cases, clustered cases (cases with M. tuberculosis isolates having identical fingerprint patterns), and cases in specific subgroups with high rates of clustering (persons born in the United States and HIV-infected persons) were examined. RESULTS: Annual tuberculosis case rates peaked at 51.2 cases per 100,000 persons in 1992 and decreased significantly thereafter to 29.8 cases per 100,000 persons in 1997 (P < 0.001). The rate of clustered cases decreased significantly over time in the entire study sample (from 10.4 cases per 100,000 persons in 1991 to 3.8 cases per 100,000 persons in 1997 [P < 0.001]), in persons born in the United States (P < 0.001), and in HIV-infected persons (P = 0.003). CONCLUSIONS: The rates of tuberculosis cases and clustered tuberculosis cases decreased both overall and among persons in high-risk groups. This occurred in a period during which tuberculosis control measures were intensified.

AIDS-Related Opportunistic Infections↗
PubMed1999

Comparative genomics of BCG vaccines by whole-genome DNA microarray.

Bacille Calmette-Guérin (BCG) vaccines are live attenuated strains of Mycobacterium bovis administered to prevent tuberculosis. To better understand the differences between M. tuberculosis, M. bovis, and the various BCG daughter strains, their genomic compositions were studied by performing comparative hybridization experiments on a DNA microarray. Regions deleted from BCG vaccines relative to the virulent M. tuberculosis H37Rv reference strain were confirmed by sequencing across the missing segment of the H37Rv genome. Eleven regions (encompassing 91 open reading frames) of H37Rv were found that were absent from one or more virulent strains of M. bovis. Five additional regions representing 38 open reading frames were present in M. bovis but absent from some or all BCG strains; this is evidence for the ongoing evolution of BCG strains since their original derivation. A precise understanding of the genetic differences between closely related Mycobacteria suggests rational approaches to the design of improved diagnostics and vaccines.

BCG Vaccine↗
PubMed1999

A historical and molecular phylogeny of BCG strains.

Bacillus Calmette-Guérin (BCG) is the name given to a family of vaccines derived in 1921 by the in-vitro attenuation of Mycobacterium bovis. Subsequently, BCG seed lots were distributed globally, and both phenotypic and genotypic differences between strains have been described. As a step to understanding BCG diversity, we have reviewed the English and French historical record on 13 strains and DNA was extracted from these strains for restriction-fragment-length-polymorphism study. The written record suggests "early strains" obtained from the Pasteur Institute between 1924 and 1926 and "later strains" obtained after 1931. Molecular typing resulted in 3 clades, based on variability in IS6110-typing and the presence of mpt64 gene. With two exceptions, these clades correspond with strains obtained in 1924-26 (IS6110-2/mpt64+), 1926-31 (IS6110-1/mpt64+), and 1931 or later (IS6110-1/mpt64-) This analysis demonstrates that BCG has undergone genetic changes since 1921, consistent with ongoing in-vitro evolution.

BCG Vaccine↗
PubMed1999

Transmission of Mycobacterium tuberculosis from patients smear-negative for acid-fast bacilli.

BACKGROUND: The microscopic examination of sputum for acid-fast bacilli, is a simple and rapid test that is used to provide a presumptive diagnosis of infectious tuberculosis. While patients with tuberculosis with sputum smears negative for acid-fast bacilli are less infectious than those with positive smears, both theoretical and empirical evidence suggest that they can still transmit Mycobacterium tuberculosis. We aimed to estimate the risk of transmission from smear-negative individuals. METHODS: As part of an ongoing study of the molecular epidemiology of tuberculosis in San Francisco, patients with tuberculosis with mycobacterial isolates with the same DNA fingerprint were assigned to clusters that were assumed to have involved recent transmission. Secondary cases with tuberculosis, whose mycobacterial isolates had the same DNA, were linked to their presumed source case to estimate transmission from smear-negative patients. Sensitivity analyses were done to assess potential bias due to misclassification of source cases, unidentified source cases, and HIV-1 co-infection. FINDINGS: 1574 patients with culture-positive tuberculosis were reported and DNA fingerprints were available for 1359 (86%) of these patients. Of the 71 clusters of patients infected with strains that had matching fingerprints, 28 (39% [95% CI 28-52]) had a smear-negative putative source. There were 183 secondary cases in these 71 clusters, of whom a minimum of 32 were attributed to infection by smear-negative patients (17% [12-24]). The relative transmission rate of smear-negative compared with smear-positive patients was calculated as 0.22 (95% CI 0.16-0.32). Sensitivity analyses and stratification for HIV-1 status had no impact on these estimates. INTERPRETATION: In San Francisco, the acid-fast-bacilli smear identifies the most infectious patients, but patients with smear-negative culture-positive tuberculosis appear responsible for about 17% of tuberculosis transmission.

AIDS-Related Opportunistic Infections↗
PubMed1999

Tuberculosis epidemiology and control in Veracruz, Mexico.

BACKGROUND: Tuberculosis (TB) rates remain high in regions of Southern Mexico despite the existence of a National Tuberculosis Program. Understanding TB epidemiology in such settings would assist in the design of improved TB control and highlight the challenges confronting TB control in developing countries. METHODS: We conducted a retrospective review of treatment control cards from 1991 to 1994 in five municipalities in a semiurban region of Southern Mexico. RESULTS: The relatively high rate of TB observed, 42.6 per 100,000 inhabitants, did not change significantly during the study period. Cure rates among new cases were 79% and significantly lower among retreatment cases (62%). Directly observed therapy (DOT) was administered to 84% of patients. Approximately one-half of the retreatment cases who were not cured were compliant with therapy, suggesting that drug resistance contributed to these poor results. Of particular concern was a core group of 16 patients who had received at least three treatments. CONCLUSIONS: This region of Mexico has persistently high TB rates despite a DOT-based TB control programme which achieves an overall cure rate of 77%. There exist many retreatment cases for whom cure rates are significantly lower. These cases may serve as a core group for the dissemination of drug resistant TB. The control programme is being reinforced by a nominal register of patients, decreasing administrative barriers for drug supply to individual patients and the availability of mycobacteria cultures. In addition to these measures, in regions which are approaching the levels of efficacy recommended by the WHO it may be appropriate to consider focusing efforts on the identification and treatment of chronic cases.

Adolescent↗
PubMed1999

Molecular epidemiologic evaluation of transmissibility and virulence of Mycobacterium tuberculosis.

Discovery of genotypic markers associated with increased transmissibility in Mycobacterium tuberculosis would represent an important step in advancing mycobacterial virulence studies. M. tuberculosis strains may be classified into one of three genotypes on the basis of the presence of specific nucleotide substitutions in codon 463 of the katG gene (katG-463) and codon 95 of the gyrA gene (gyrA-95). It has previously been reported that two of these three genotypes are associated with increased IS6110-based clustering, a potential proxy of virulence. We designed a case-control analysis of U.S.-born patients with tuberculosis in San Francisco, Calif., between 1991 and 1997 to investigate associations between katG-463 and gyrA-95 genotypes and epidemiologically determined measures of strain-specific infectivity and pathogenicity and IS6110-based clustering status. We used a new class of molecular probes called molecular beacons to genotype the isolates rapidly. Infectivity was defined as the propensity of isolates to cause tuberculin skin test conversions among named contacts, and pathogenicity was defined as their propensity to cause active disease among named contacts. The molecular beacon assay was a simple and reproducible method for the detection of known single nucleotide polymorphisms in large numbers of clinical M. tuberculosis isolates. The results showed that no genotype of the katG-463- and gyrA-95-based classification system was associated with increased infectivity and pathogenicity or with increased IS6110-based clustering in San Francisco during the study period. We speculate that molecular epidemiologic studies investigating clinically relevant outcomes may contribute to the knowledge of the significance of laboratory-derived virulence factors in the propagation of tuberculosis in human communities.

AIDS-Related Opportunistic Infections↗
PubMed1999

Use of pulsed-field gel electrophoresis for molecular epidemiologic and population genetic studies of Mycobacterium tuberculosis.

Pulsed-field gel electrophoresis (PFGE) is a powerful molecular biology technique which has provided important insights into the epidemiology and population biology of many pathogens. However, few studies have used PFGE for the molecular epidemiology of Mycobacterium tuberculosis. A laboratory protocol was developed to determine the typeability, stability, and reproducibility of PFGE typing of M. tuberculosis. Formal data-analytical techniques were used to assess the genetic diversity elucidated by PFGE analyses using four separate restriction enzymes and by IS6110 RFLP analyses, as well as to assess the concordance among these typing methods. One hundred epidemiologically characterized clinical isolates of M. tuberculosis were genotyped with four different PFGE enzymes (AseI, DraI, SpeI, and XbaI), as well as by RFLP analysis with IS6110. Identical patterns were found among 34 isolates known to be genetically related, suggesting that the PFGE protocol is robust and reproducible. Among 66 isolates representing population-sampled cases, heterozygosity and information content dependency estimates indicate that all five genotyping systems capture quantitatively similar levels of genetic diversity. Nevertheless, comparisons between PFGE analyses and IS6110 typing reveals that PFGE provided more discrimination among isolates with fewer than five copies of IS6110 and less clustering in isolates with five or more copies. The comparisons confirm the hypothesis that the resolution of IS6110 RFLP genotyping is dependent upon the number of IS6110 elements in the genome of isolates. The general concordance among the results obtained with four independent enzymes suggests that M. tuberculosis is a clonal organism. The availability of a robust genotyping technique largely independent of repetitive elements has implications for the molecular epidemiology of M. tuberculosis.

DNA Transposable Elements↗
PubMed1999

Tuberculosis in the 21st century: DOTS and SPOTS. Plenary lecture given at the 29th World Conference of the International Union Against Tuberculosis and Lung Disease, Bangkok, Thailand, 23-26 November 1998. Directly observed therapy.

Surveys of the global burden of disease have established that formidable health problems loom as the new millennium approaches. In both industrialized and developing countries lung disease is particularly problematic. Tuberculosis provides a concrete example of the ability of existing interventions such as directly observed therapy (DOT) to save millions of lives in the immediate future and the potential for new knowledge and tools to eventually eliminate the disease. Molecular epidemiology shows the potential of new technology to supplement established approaches in answering questions central to public health. Our knowledge of the complete genomic sequence of Mycobacterium tuberculosis now has us poised on the brink of a new era. Emerging technologies such as microscopic arrays comprised of thousands of spots of DNA will provide knowledge that will fundamentally alter our approach to disease control. The synergy of a balanced portfolio incorporating a globalized public health commitment and creative basic research will provide us with the infrastructure and tools needed to eliminate tuberculosis before the close of the 21st century.

Communicable Disease Control↗