Joseph H. Bates

Identification of Risk Factors for Extrapulmonary Tuberculosis

The proportion of extrapulmonary tuberculosis cases in the United States has increased from 16% of tuberculosis cases, in 1991, to 20%, in 2001. To determine associations between the demographic, clinical, and life style characteristics of patients with tuberculosis and the occurrence of extrapulmonary tuberculosis, a retrospective case-control study was conducted. This study included 705 patients with tuberculosis, representing 98% of the culture-proven cases of tuberculosis in Arkansas from 1 January 1996 through 31 December 2000. A comparison between 85 patients with extrapulmonary tuberculosis (case patients) and 620 patients with pulmonary tuberculosis (control patients) showed women (OR, 1.98; 95% CI, 1.25-3.13), non-Hispanic blacks (OR, 2.38; 95% CI, 1.42-3.97), and HIV-positive persons (OR, 4.93; 95% CI, 1.95-12.46) to have a significantly higher risk for extrapulmonary tuberculosis than men, non-Hispanic whites, and HIV-negative persons. This study expands the knowledge base regarding the epidemiology of extrapulmonary tuberculosis and enhances our understanding of the relative contribution of host-related factors to the pathogenesis of tuberculosis.

IS6110: Conservation of sequence in the Mycobacterium tuberculosis complex and its utilization in DNA fingerprinting

Multiple copies of an insertion sequence, IS6110, were shown to be present in the genome of members of the Mycobacterium tuberculosis complex (M. tuberculosis and M. bovis). Ten to 12 copies are present in various strains of M. tuberculosis, while strains of M. bovis contain only one to three copies. IS6110 was not detected in the DNA of other species of mycobacteria. Restriction endonuclease analysis indicated that the sequence of IS6110 is conserved across strain and species lines. Hybridization to the insertion sequence can be used to detect restriction fragment length polymorphism reflecting divergence in the sequence of regions flanking the various copies of IS6110. These differences were used to fingerprint various strains of the M. tuberculosis complex.

Interpretation of Restriction Fragment Length Polymorphism Analysis of Mycobacterium tuberculosis Isolates from a State with a Large Rural Population

Epidemiologic relatedness of Mycobacterium tuberculosis isolates from Arkansas residents diagnosed with tuberculosis in 1992-1993 was assessed using IS6110- and pTBN12-based restriction fragment length polymorphism (RFLP) and epidemiologic investigation. Patients with isolates having similar IS6110 patterns had medical records reviewed and were interviewed to identify epidemiologic links. Complete RFLP analyses were obtained for isolates of 235 patients; 78 (33%) matched the pattern of > or = 1 other isolate, forming 24 clusters. Epidemiologic connections were found for 33 (42%) of 78 patients in 11 clusters. Transmission of M. tuberculosis likely occurred many years in the past for 5 patients in 2 clusters. Of clusters based only on IS6110 analyses, those with > or = 6 IS6110 copies had both a significantly greater proportion of isolates that matched by pTBN12 analysis and patients with epidemiologic connections, indicating IS6110 patterns with few bands lack strain specificity. Secondary RFLP analysis increased specificity, but most clustered patients still did not appear to be epidemiologically related. RFLP clustering in rural areas may not represent recent transmission.

The history of tuberculosis as a global epidemic

TB should be thought of as a slowly progressing worldwide epidemic. Initially it was a disease of lower mammals, and the etiologic agent probably preceded the development of man on earth. It became an uncommon endemic disease in man about the time man began to settle in villages and develop agriculture. Crowding in European cities, and later the industrial revolution in Europe, provided the necessary environmental conditions for the endemic disease to become epidemic. For the next 400 years, the disease was spread by European empire-building and colonization. It came late to sub-Saharan Africa and to the Pacific Islands, and still later to the highlands of New Guinea. The epidemic gradually wanes within a large population group as resistant individuals survive and reproduce. This natural resistance is reflected in the ability of the macrophage to control intracellular growth of the organism. The resistant host shows a chronic infection primarily affecting the lungs, whereas the highly susceptible host shows a rapidly fatal illness with generalized spread of disease to many organs. Survivors of the initial infection then show another type of resistance to reinfection that is based on sensitized T cells. When this system is only partially successful, the host becomes infectious and capable of spreading the infection widely. The study of the epidemiology of TB and the evaluation of various public health measures to prevent or contain the disease requires that the investigator have an understanding of the nature and duration of the TB epidemic in the particular population under study. This factor is a much greater determinant of the course of an epidemic than any public health measure that man can institute, just as the currents in a river can have a more powerful effect on the course of a canoe than the most vigorous paddler.

Association between Mycobacterium tuberculosis Beijing/W Lineage Strain Infection and Extrathoracic Tuberculosis: Insights from Epidemiologic and Clinical Characterization of the Three Principal Genetic Groups of M. tuberculosis Clinical Isolates

ABSTRACT Clinical strains of Mycobacterium tuberculosis can be divided into three principal genetic groups based on the single-nucleotide polymorphisms at the katG gene codon 463 and the gyrA gene codon 95. One subgroup of genetic group 1, the Beijing/W lineage, has been widely studied because of its worldwide distribution and association with outbreaks. In order to increase our understanding of the clinical and epidemiological relevance of the genetic grouping of M. tuberculosis clinical strains and the Beijing/W lineage, we investigated the genetic grouping of 679 clinical isolates of M. tuberculosis, representing 96.3% of culture-confirmed tuberculosis cases diagnosed in Arkansas between January 1996 and December 2000 using PCR and DNA sequencing. We assessed the associations of infections by different genetic groups of M. tuberculosis strains and infection by the Beijing/W lineage strains with the clinical and epidemiological characteristics of the patients using chi-square tests and multivariate logistic regression analysis. Of the 679 study isolates, 676 fell into one of the three principal genetic groups, with 63 (9.3%) in group 1, 438 (64.8%) in group 2, and 175 (25.9%) in group 3. After adjusting for potential confounding of age, gender, race/ethnicity, human immunodeficiency virus serostatus, and plcD genotype in a multivariate logistic regression model, patients infected by the Beijing/W lineage isolates were nearly three times as likely as patients infected with the non-Beijing/W lineage isolates to have an extrathoracic involvement (odds ratio [95% confidence interval], 2.85 [1.33, 6.12]). Thus, the Beijing/W lineage strains may have some special biological features that facilitate the development of extrathoracic tuberculosis.

The Risk for Transmission of Mycobacterium tuberculosis at the Bedside and during Autopsy

Tuberculosis is generally not considered highly communicable. A recent experience shows the great variation in the infectiousness of a patient with tuberculosis. Case Report A 57-year-old man was hospitalized for increasing dizziness, decreased oral intake, and a weight loss of 11 kg within 6 months. His medical history included anemia and adenocarcinoma of the prostate that was treated with radical prostatectomy and radiation. He had abused alcohol and tobacco for many years but denied exposure to tuberculosis. The patient was cachectic but alert and cooperative. His temperature was 36.4 C, his pulse was 126 beats/min, his respiration rate was 20 breaths/min, and his blood pressure was 110/70 mm Hg when he was supine and sitting but 90/60 mm Hg when he was standing. Percussion and auscultation indicated that his lungs were clear and that his abdomen was soft and nontender with normal bowel sounds. A chest radiograph showed no abnormality of the heart or lungs. Laboratory findings were as follows: hematocrit, 24.7%; leukocyte count, 5.7 109/L; and hemoglobin level, 8.2 g/dL. Admission diagnosis was postural hypotension secondary to autonomic dysfunction, with dehydration playing a contributory role. Comorbid conditions included a normochromic, normocytic anemia. No recognizable infection was present, nor was there evidence for recurrent malignancy. On the sixth hospital day, a urinary tract infection developed that was caused by Streptococcus faecalis and that responded promptly to intravenous antibiotics. On hospital day 16, the patient gradually became dyspneic and less responsive. Moderate ascites was noted, and a chest radiograph showed cephalization of the pulmonary vasculature and diffuse bilateral pulmonary infiltration with bilateral pleural effusions. Examination of the ascitic fluid showed a leukocyte count of 1 109/L, an erythrocyte count of 120 cells/mm3, an amylase level of 0.32 kat/L, a glucose level of 6.4 mmol/L, a protein level of 24 g/L, and a lactate dehydrogenase level of 5.23 kat/L. Gram, fluorochrome, and Ziehl-Neelson stains of the ascitic fluid were negative. Intradermal skin tests with 5 tuberculin units of purified protein derivative and two control antigens gave no reaction at 48 hours. The serum was negative for antibody to human immunodeficiency virus. The ascites, pulmonary infiltration, and pleural effusions were thought to be caused by congestive heart failure or hepatic cirrhosis. The patient continued to deteriorate and died on hospital day 21. An autopsy was then done. Postmortem Examination Examination of the lungs showed extensive pneumonia with large areas of necrosis, but no granulomas were noted. Hundreds of tubercle bacilli were seen in every oil immersion field of the lung, hilar lymph nodes, spleen, peritoneum, kidneys, testes, brain, and vertebral bodies. Culture of all tissues showed heavy growth of Mycobacterium tuberculosis. Cultures of blood and ascitic fluid obtained 5 days before death were positive for M. tuberculosis and were sensitive to all drugs tested. Epidemiologic Investigation When it was realized that the patient had died of tuberculosis, an epidemiologic investigation was initiated. Fortunately, for several years our medical center has tested all new clinical personnel with the two-step Mantoux method using 5 tuberculin units of purified protein derivative. Nonreactors are retested annually. An induration of greater than 10 mm 48 hours after the test is considered a positive result. During the patients 21-day hospital stay, 47 health care workers participated in his care. Of these, 7 (14.9%) were known positive tuberculin reactors and 40 were nonreactors. Because the diagnosis of tuberculosis had not been suspected, no respiratory precautions had been taken. The patient was in a single room with ventilation that provided five fresh-air changes per hour but no upper-air sterilization with ultraviolet irradiation. On repeat tuberculin testing 8 weeks after the patients death, none of the 40 nonreactors had converted to positive, and none was treated. The findings for personnel in the autopsy room differed from the findings for the personnel who had cared for the patient (Table 1). Of the 10 persons in the room, 5 were already k Table 1. Duration of Exposure and Results of Clinical Evaluation and Treatment for Staff and Students Present at Autopsy*

Population-Based Study of Deletions in Five Different Genomic Regions of Mycobacterium tuberculosis and Possible Clinical Relevance of the Deletions

ABSTRACT Regions of difference (RDs) have been described in clinical isolates of Mycobacterium tuberculosis, but the potential epidemiological and clinical relevance of the genotypes of these RDs remains to be investigated. We screened a population-based sample of 648 isolates for the deletion of five RDs, designated RD105, RD181, RD142, RD150, and RD239, using microarray-based hybridization, PCR, and DNA sequencing and assessed the associations between the RD deletions and the clinical characteristics of the patients using chi-square analysis and multivariate logistic regression model. Of the 648 isolates, 18 (2.8%) had the RD239 deletion and 39 (6.0%) had the RD105 deletion. The deletions of RD142, RD150, and RD181 subdivided the isolates with the RD105 deletion into four groups comprising a group with concurrent deletions of RD105, RD181, and RD142 (n = 13); a group with concurrent deletions of RD105, RD181, and RD150 (n = 5); a group with concurrent deletions of RD105 and RD181 (n = 13); and a group with a deletion of RD105 only (n = 8). Extrathoracic tuberculosis is statistically significantly associated with infection with the isolates with concurrent deletions of RD105, RD181, and RD142 (adjusted odds ratio [OR] = 3.05; 95% confidence interval [CI] = 1.58, 5.90) and the isolates with concurrent deletions of RD105, RD181, and RD150 (adjusted OR = 11.09; 95% CI = 4.27, 28.80), after controlling for the previously identified risk factors for extrathoracic tuberculosis (human immunodeficiency virus serostatus, race, gender, and the genotype of the plcD gene). These two combinations of RD deletions have the potential for predicting the clinical presentation of M. tuberculosis infection in the human host.

Evidence of a "silent" bacillemia in primary tuberculosis.

Abstract A case is described in which a chest-wall abscess appears to have developed during the course of a silent primary tuberculous infection caused by localization of bacilli in the site of blu...

Unrecognized Tuberculosis in a Nursing Home Causing Death with Spread of Tuberculosis to the Community

OBJECTIVES: To determine the reason for an increase in tuberculin skin test (TST) conversion in employees in a nursing home and to determine the source case responsible for spread of tuberculosis (TB) in two nursing homes and a hospital in a rural part of Arkansas using molecular and traditional epidemiological methods.

Mycobacterium tuberculosis transmission between cluster members with similar fingerprint patterns.

Molecular epidemiologic studies provide evidence of transmission of Mycobacterium tuberculosis within clusters of patients whose isolates share identical IS6110-DNA fingerprint patterns. However, M. tuberculosis transmission among patients whose isolates have similar but not identical DNA fingerprint patterns (i.e., differing by a single band) has not been well documented. We used DNA fingerprinting, combined with conventional epidemiology, to show unsuspected patterns of tuberculosis transmission associated with three public bars in the same city. Among clustered TB cases, DNA fingerprinting analysis of isolates with similar and identical fingerprints helped us discover epidemiologic links missed during routine tuberculosis contact investigations.