A hypothesis for the existence of two types of tuberculosis, reflecting two distinct types of immune failure to control the pathogen, based upon prevalence of mycobacterium-specific IgG subclasses.

Most people infected by Mycobacterium tuberculosis, about 90%, contain the pathogen and are healthy. Most investigators have concluded that pathogen-specific Th1 cells contribute to protection. Pulmonary tuberculosis, the most prevalent form of disease, is associated with destructive granulomas, the formation of which also appears to involve Th1 cells. In what sense then do the two Th1 components of the response, in healthy infected individuals and patients, differ? An insight into this question might provide clues for attaining effective vaccination and better treatment. We approached this question by examining the relative prevalence of different IgG isotypes among anti-mycobacterium-specific antibodies in patients and healthy infected individuals as a surrogate marker for the Th1/Th2 phenotype of the response. Our observations lead us to agree that healthy infected individuals generate a predominant Th1 response. Our observations also lead us to propose that many patients make a similar kind of response as healthy infected individuals, but that this response is too weak to contain the infection. We refer to such individuals as having type I tuberculosis. Other patients appear to have a greater and detrimental Th2 component to their immune response than that of healthy infected individuals. We refer to these individuals as having type II tuberculosis. This proposal that there are two types of tuberculosis, reflecting two distinct types of failure by the immune system, will, if correct, be pertinent to vaccine design, treatment of tuberculosis and in making further progress in our understanding the genetics of susceptibility to M. tuberculosis.

Local epidemic history as a predictor of tuberculosis incidence in Saskatchewan Aboriginal communities.

BACKGROUND: Average tuberculosis (TB) incidence rates are high in Canadian Aboriginal communities, but there is significant variability within this group. OBJECTIVE: To determine whether local history of post-contact TB epidemics is predictive of contemporary epidemiology among Aboriginal communities in Saskatchewan, Canada. METHODS: TB incidence, age-specific morbidity patterns and rates of clustering of TB genotypes from 1986 to 2004 were compared between two groups of communities: Group 1, in which post-contact epidemics of TB were established around 1870, and Group 2, in which they were delayed until after 1920. Concomitant effects of socio-economic and geographic variables were explored with multivariate models. RESULTS: Group 2 communities were characterized by higher annual incidence of TB (median 431 per 100,000 population vs. 38/100,000). In multivariate models that included socio-economic and geographic variables, historical grouping remained a significant independent predictor of community incidence of TB. Clustering of TB genotypes was associated with Group 2 (OR 8.7, 95%CI 3.3-22.7) and age 10-34 years (OR 2.5, 95%CI 1.1-5.7). CONCLUSIONS: TB transmission dynamics can vary significantly as a function of a population's historical experience with TB. Populations at different stages along the epidemic trajectory may be amenable to different types of interventions.

Treatment outcome of multidrug-resistant tuberculosis among Vietnamese immigrants.

OBJECTIVE: To review the outcome for MDR-TB treatment among potential migrants from Vietnam. SETTING: All cases of documented MDR-TB treated by the International Organization of Migration (IOM) in Vietnam from 1989 to 2000 were reviewed. METHODS: MDR-TB was defined as isoniazid- and rifampicin-resistant Mycobacterium tuberculosis. All cases of TB treated by the IOM and recorded in the computerised database were reviewed to identify MDR-TB cases. Demographics, chest radiograph results, drug resistance, drug use and dosage, duration of treatment, and outcome were analysed. RESULTS: Forty-four cases of MDR-TB were identified. Treatment consisted of ambulatory directly observed treatment with an 8-drug protocol: isoniazid, rifampicin, pyrazinamide, ethambutol, capreomycin, ethionamide, ofloxacin and cycloserine. This initial protocol was modified due to drug availability or drug intolerance. Patients were treated with a median of 8 drugs (range 6-12). Mean duration of treatment for MDR-TB was 23.0 (SD+/-11.4) months. Thirty-eight (86%) patients were cured and emigrated, one failed treatment (2%), three were lost to follow-up (7%) and two died (4%). CONCLUSION: Treatment for MDR-TB provided by the IOM was effective in preparing a low-income population for migration.

Extent of pulmonary tuberculosis in patients diagnosed by active compared to passive case finding.

OBJECTIVE: To compare the extent of pulmonary tuberculosis amongst patients detected by screening (active case finding) with that in patients detected by symptoms (passive case finding), and to identify early symptoms of pulmonary tuberculosis. SUBJECTS AND METHOD: In this cross-sectional study, Tuberculosis Control Program records were reviewed for method of detection and extent of disease in Canadian Plains Aborigines between 1 January 1991 and 30 June 1999. RESULTS: Among 903 cases, method of detection was active in 450 (49.8%) and passive in 453 (50.2%). Cough and fever were the most common symptoms in both methods of detection, and were significantly more frequent in passive detection (P < 0.05). Cough was present in 59% and fever in 19% of actively detected cases compared to 84% and 47%, respectively, of passively detected cases. Age was significantly different between the two methods of detection. Hemoptysis, weight loss and method of detection were associated with increased risk of infectiousness among those < or = 19 years, while cough, hemoptysis and weight loss were associated among those >19 years. CONCLUSION: Method of detection rather than age contributed to infectiousness in children and adolescents. Daily cough for more than 1 month and unexplained fever for more than 1 week should raise the suspicion for TB.

Twice weekly isoniazid and rifampin treatment of latent tuberculosis infection in Canadian plains Aborigines.

Six months of twice weekly directly observed isoniazid and rifam-picin treatment of latent tuberculosis (TB) infection was implemented to improve the outcome of treatment. A total of 591 infected aborigines without previous tuberculosis or treatment of latent TB infection received twice weekly isoniazid and rifampicin for 6 mo from 1992 to 1995. The outcome was compared with 403 infected aborigines without previous tuberculosis or treatment of latent TB infection who received self-administered isoniazid daily for 1 yr from 1986 to 1989. Of patients, 487 (82%) completed the twice weekly 6-mo regimen compared with 77 (19%) who completed the daily 12-mo regimen. The main reason for incomplete treatment was default. Both groups were followed over a 6-yr period. The rate of tuberculosis in the twice-weekly isoniazid and rifampicin-treated patients was 0.9/1,000 patient-years compared with 9/1,000 patient-years in the daily isoniazid-treated patients. The rate of side effects was higher for directly observed treatment patients, 136/1,000 patient-years of drugs, compared with 39/ 1,000 patient-years for self-administered treatment patients. Life-threatening side effects such as skin allergic reactions and hepatitis were the same in both groups. A regimen of 52 doses of directly observed twice weekly isoniazid and rifampicin is an effective and well-tolerated regimen to improve the outcome of the treatment of latent tuberculosis infection in a population with a high rate of default with daily self-administered isoniazid.

Tuberculosis in aboriginal Canadians.

Endemic tuberculosis (TB) was almost certainly present in Canadian aboriginal people (aboriginal Canadians denotes status Indians, Inuit, nonstatus Indians and metis as reported by Statistics Canada) before the Old World traders arrived. However, the social changes that resulted from contact with these traders created the conditions that converted endemic TB into epidemic TB. The incidence of TB varied inversely with the time interval from this cultural collision, which began on the east coast in the 16th century and ended in the Northern Territories in the 20th century. This relatively recent epidemic explains why the disease is more frequent in aboriginal children than in Canadian-born nonaboriginal people. Treatment plans must account for the socioeconomic conditions and cultural characteristics of the aboriginal people, especially healing models and language. Prevention includes bacillus Calmette-Guerin vaccination and chemoprophylaxis, and must account for community conditions, such as rates of suicide, which have exceeded the rate of TB. The control of TB requires a centralized program with specifically directed funding. It must include a program that works in partnership with aboriginal communities.

Detection of pulmonary tuberculosis in patients with a normal chest radiograph.

OBJECTIVES: To describe the early symptoms of pulmonary tuberculosis (TB) when the chest radiograph (CXR) is normal. SETTING: Centralized, provincial TB control program. SUBJECTS: Twenty-five patients with culture-positive pulmonary TB and a normal CXR were identified from a review of 518 consecutive patients with culture-positive pulmonary TB in the province of Saskatchewan from January 1, 1988 to March 31, 1997. Patients with abnormal CXRs at the time of diagnosis were excluded from the analysis. RESULTS: Twenty-three of the 25 patients (92%) were symptomatic at the time of diagnosis, with cough/sputum (76%) being reported most commonly. Eleven patients were identified because of contact tracing from cases of infectious pulmonary TB, while the other 14 patients were identified because of an investigation of symptoms. Twenty-four patients (96%) exhibited one or more symptoms of cough for > 1 month, fever for > 1 week, or skin-test conversion after contact with infectious TB. The sputum smear of only one patient was positive. Two patients were pregnant at the time of diagnosis, one patient was HIV-positive, and one patient demonstrated isoniazid-resistant organisms on sensitivity testing. Five patients were diagnosed as having primary TB associated with Mantoux skin-test conversion. The incidence of culture-positive pulmonary TB with a normal chest radiograph was < 1% in the period from 1988 to 1989 and steadily increased to 10% in the period from 1996 to 1997. CONCLUSIONS: Culture-positive pulmonary TB with a normal CXR is not uncommon, and the incidence of this presentation is increasing. Patients with this presentation of TB are typically symptomatic and/or are detected by contact tracing to infectious cases of pulmonary TB. The results suggest that patients presenting with a cough for > 1 month, with a fever for > 1 week, or with documented skin-test conversion < 2 years after known exposure to infectious TB should have sputum submitted for a Mycobacterium tuberculosis smear and culture despite a normal CXR.

Miliary Mycobacterium bovis induced by intravesical bacille Calmette-Guérin immunotherapy.

Intravesical instillation of bacille Calmette-Guérin (BCG), an attenuated strain of Mycobacterium bovis, is the treatment of choice for many patients with bladder cancer. In a small percentage, this therapy is associated with systemic side effects including pneumonitis. It is uncertain whether these systemic manifestations are due to dissemination of infection or due to hypersensitivity, an etiologic distinction that has important therapeutic implications. We report the first case in which miliary M. bovis was proven to be the responsible mechanism, by culture of M. bovis biovar BCG from a transbronchial lung biopsy and complete resolution on anti-tuberculous chemotherapy.

Prediction of nonresponse to corticosteroids in stable chronic airflow limitation.

The efficacy of corticosteroids in chronic airflow limitation is variable and nonpredictable. We believe that the corticosteroid-induced improvement seen in a few subjects with chronic airflow limitation indicates coexistent bronchial asthma. Therefore, we hypothesize that by carefully excluding all features (other than corticosteroid response), either objective or subjective, that might be consistent with coexisting asthma, we could predict non-response to corticosteroids. Twenty patients with chronic airflow limitation related to cigarette smoking were chosen. Features that might suggest coexisting asthma were carefully excluded; these included rhinitis, nocturnal symptoms, atopy, large response to bronchodilator, and sputum or blood eosinophilia. Eighteen of these 20 subjects completed a double-blind random-order cross-over placebo-controlled trial of 30 mg of prednisone for 14 d (with a 14 d washout between treatments). There were no significant differences, individually or collectively, in objective or subjective determinations. Based on a greater than or equal to 250 mL improvement in FEV1, there were two placebo responders and two prednisone responders. Although it may be difficult to predict corticosteroid response in chronic airflow limitation, it appears that careful exclusion of 'asthmatic tendencies' may predict nonresponse to corticosteroids.

The outcome of chemoprophylaxis on tuberculosis prevention in the Canadian Plains Indian.

A 1986 audit of self-administered anti-tuberculous prophylaxis (SAP) revealed a compliance rate of 25% at six weeks, 8% at 16 weeks, and 5% at 52 weeks. A short affordable program of daily observed prophylaxis (DOP) and education was developed to improve the compliance rate. The sustaining influence of a six week intervention on one year of prophylaxis was determined. Forty-two of 114 (37%) eligible patients began chemoprophylaxis and were randomly assigned to two groups - 21 in Group 1 with DOP and education, and 21 in Group 2 with SAP and education. After six weeks, Group 1 compliance was greater than 1986 compliance (p less than 0.001) and greater than Group 2 compliance (p less than 0.05), and Group 2 compliance was greater than 1986 compliance (p less than 0.01). At 16 weeks, 10 weeks after DOP and education were discontinued, the compliance of the three groups was not different. Since 63% of persons who represent potential future tuberculosis were lost in the evaluation process before starting preventive treatment, and 5% of those who began preventive treatment completed treatment, only 2% of potential future tuberculosis was prevented. DOP and education significantly improved compliance but the improvements were not sustained after DOP and education were discontinued.

Superficial mycobacterial lymphadenitis in Saskatchewan.

A total of 43 bacteriologically verified cases of superficial mycobacterial lymphadenitis were reported in Saskatchewan between 1981 and 1986; 35 (81%) were due to Mycobacterium tuberculosis. Among the eight cases (19%) due to nontuberculous mycobacteria the agent most frequently isolated was M. avium-intracellulare. Five additional cases were smear-positive and culture-negative. Direct smears of node tissue or aspirate were positive for acid-fast bacilli in 7 (88%) of the 8 cases of nontuberculous mycobacterial lymphadenitis but in only 16 (46%) of the 35 cases due to M. tuberculosis. Superficial tuberculous lymphadenitis was most frequent in female North American Indian or Asian-born adults and most commonly involved the cervical nodes. Nontuberculous mycobacterial lymphadenitis was most frequent in female white children, and most commonly involved the submandibular nodes. The cases of both tuberculous and nontuberculous mycobacterial lymphadenitis were spread throughout the province. There was an urban concentration of cases of tuberculous lymphadenitis in those of Asian origin. It is important to distinguish between superficial mycobacterial lymphadenitis due to M. tuberculosis and that due to nontuberculous mycobacteria for treatment and management purposes.

Tuberculosis in chronic care homes.

Caucasian Canadians are in the tertiary phase of a 300-year tuberculosis epidemic. In this phase, the pattern of disease over the age spectrum is low in the young and middle-aged groups and rises to four times this rate in the elderly. The concentration of the elderly in chronic care homes (CCHs) magnifies the tuberculosis problem by increasing case rates another four times above the rate of elderly persons living separately, and 20 times above the overall Canadian rate. In spite of effective drugs with cure rates of over 95%, tuberculosis in the institutionalized elderly continues at an alarming rate. The difficulty lies in case finding. The prevailing attitude is that tuberculosis is no longer a problem. Surveillance programs are rudimentary. Between 35% and 40% of active cases in CCHs are the result of primary infection, mimicking bacterial pneumonia clinically and radiographically. In this target group of high-incidence tuberculosis, surveillance of residents is necessary, and the diagnosis needs to be considered in antibiotic-unresponsive pneumonia and in fever of unknown origin.

Nighttime ventilation improves respiratory failure in secondary kyphoscoliosis.

Four patients with cardiorespiratory failure caused by secondary kyphoscoliosis were studied. Polycythemia, cor pulmonale, restrictive lung pattern (functional residual capacity (FRC), 17 to 27% predicted; vital capacity (VC), 11 to 23% predicted), and abnormal arterial blood gases, primarily hypoventilation (PaO2, 31 to 44 mm Hg; PaCO2, 52 to 73 mm Hg), were seen in all. Supplementary oxygen, digoxin, diuretics, 15 min of intermittent positive-pressure breathing with inspired pressure (PI) 25 cm H2O 4 times daily, and tracheostomy failed to produce improvement. However, 12 h of nighttime ventilation (NTV) with PI 28 to 35 cm H2O through a permanent tracheostomy proved effective. Within 72 h, dyspnea at rest, restless sleep, and frequent waking resolved. Within 8 to 22 days, the PaO2 was approximately 58 mmHg and the PaCO2 was approximately 41 mm Hg while breathing 21% oxygen spontaneously during the day. The right heart failure resolved within 2 to 7 wk, and the hemoglobin count decreased to approximately 165 g/L within 2 to 6 months. There was a mean increase of 700 ml (72%) in functional residual capacity and 430 ml (49%) in vital capacity. The patients were discharged 2 days to 5 wk after NTV commenced. Daytime activity increased, approaching a normal life style. The improvement was sustained over a mean follow-up period of 3.4 yr. Problems included recurrent episodes of tracheobronchitis, mild self-limiting hemoptysis, and speech modification. Nighttime ventilation may be an effective alternative for long-term treatment of cardiorespiratory failure caused by secondary kyphoscoliosis.

Recurrent nocturnal asthma after bronchoprovocation with Western Red Cedar sawdust: association with acute increase in non-allergic bronchial responsiveness.

Recurrent nocturnal asthma following a single exposure to Western Red Cedar sawdust was documented by measurements of peak flow rates in two sensitized subjects. The nocturnal asthma followed a dual asthmatic response in the first subject and a late (non-immediate) asthmatic response in the second. Both subjects developed a 10-fold reduction in the dose of histamine required to decrease the FEV1 by 20%. This cedar-induced increase in non-specific bronchial reactivity was maximal at the time of the recurrent nocturnal asthma, and persisted after nocturnal asthma had ceased and after FEV1 had returned to normal. We hypothesize that the enhanced non-specific bronchial reactivity which occurs following late asthmatic responses to bronchial challenge is the cause of recurrent nocturnal asthma following single exposure to a sensitizing agent.

Occupational asthma caused by cedar urea formaldehyde particle board.

Two carpenters developed asthma and rhinitis related to occupational exposure to a cedar urea formaldehyde (CUF) particle board. One patient developed nasal and chest symptoms and an equivocal early asthmatic response after CUF sawdust exposure, but not after spruce or western red cedar sawdust exposure; possible late asthmatic response may have been inhibited by beclomethasone treatment. The other patient developed marked nasal and chest symptoms and a dual asthmatic response after CUF exposure, but not after spruce or cedar exposure. Both patients developed increased bronchial responsiveness to inhaled histamine, which persisted for at least six days in the first patient, and which was associated with increased asthmatic symptoms of days' to weeks' duration in both. A previously unexposed asthmatic patient, with more markedly hyperreactive bronchi, developed no symptoms, no change on spirometric testing, and no change in histamine response after CUF exposure. Specific IgE antibodies directed against formaldehyde-human serum albumin conjugate could not be demonstrated using the radioallergosorbent test. This investigation documents the occurrence of occupational asthma caused by urea formaldehyde used as a bonding agent in particle boards. Absence of a response in a previously unexposed, more severe asthmatic patient suggests specific sensitization to some component of the urea formaldehyde resin complex had developed.