Management of latent tuberculous infection in Norway in 2009: a descriptive cross-sectional study.

SETTING: Despite a steep increase in the number of individuals treated for latent tuberculous infection (LTBI), few data are available on how treatment is implemented. OBJECTIVE: To obtain baseline information on initiation and completion of treatment for LTBI in Norway in 2009. DESIGN: A descriptive cross-sectional study. RESULTS: All 721 patients treated for LTBI in 2009 in Norway were included, of whom 607 (84%) completed treatment. The treatment regimen generally consisted of 3 months of rifampicin and isoniazid. The three main reasons for starting treatment were: 1) countries of origin with high tuberculosis (TB) prevalence, 2) a positive tuberculin skin test, and 3) a positive interferon gamma release assay. The use of directly observed treatment varied by health region and age. The majority of the 34 medical specialists interviewed saw a need for new national guidelines to improve the selection of high-risk patients with LTBI. CONCLUSIONS: Management of LTBI is in accordance with current guidelines, with a high completion rate. More targeted selection of which patients should be offered preventive treatment is required, and new guidelines and tools to enhance risk assessment are necessary.

Translating childhood tuberculosis case management research into operational policies.

The control of childhood tuberculosis (TB) has been of low priority in TB programmes in high-burden settings. The objective of this paper was to describe the development and testing of tools for the management of childhood TB. The Pakistan National TB Control Programme embarked on a number of activities, including the establishment of policy guidelines for the management of childhood TB and later a guidance document, 'Case Management Desk Guide and Structured Monitoring', to demonstrate the implementation of childhood TB interventions in a programme context. Initial results showed improved case finding and treatment outcome in implementation sites compared with control districts. However, further programme attention is required to improve quality.

Diagnosis and outcome of childhood tuberculosis: implementing public health policy in three districts of Pakistan.

SETTING: All nine public sector hospitals in three districts of Pakistan. OBJECTIVE: To estimate case notifications of children with tuberculosis (TB) and their outcomes. DESIGN: A retrospective cohort following all children aged <15 years placed on TB treatment under the National TB Control Programme (NTP) in public hospitals. The study period was 2 years before and 2 years after the implementation of new NTP policy guidelines for childhood TB. Data were collected from hospital TB registers, patient treatment cards and quarterly reports. RESULTS: With the introduction of the new NTP policy, case notification of childhood TB increased from 189 (2004-2005) to 731 for the 2 years 2006-2007. The annual notification rate of childhood TB cases increased from 1.4 (2004-2005) to 5.2 per 100 000 population (2006-2007). Of the total 920 childhood TB cases registered, 610 were pulmonary, 202 extra-pulmonary and the remaining 108 unclassified. The three-fold increase in case notification was accompanied by a lack of follow-up, resulting in an increase in unknown treatment outcomes from 21.7% to 73.3%. CONCLUSION: Managing children with TB in routine NTP practice is possible, but without adequate operational guidelines, expanding services and follow-up, it can lead to suboptimal results.

How does clinical diagnosis of mycobacterial adenitis correlate with histological findings?

OBJECTIVE: To describe and compare histopathological findings with clinical criteria in diagnosis of TB adenitis. METHODS: Lymph node biopsies were obtained from 213 patients. Specimens were processed for culture and histopathologic examination, using standard methods. One hundred blocks with good preservation of tissue morphology were selected for detailed histological examination. RESULTS: About 75% of 213 patients had granulomas. In the remaining 25%, neither histopathological nor microbiological evidence of mycobacterial disease was found. Of 100 blocks selected for detailed examination, 79 blocks had granulomatous changes. The granulomas were well organised in 24%, mixed in 33%, and poorly organised in 43%. Langhans giant cells and acid-fast bacilli were observed in 88.6% and 21.5% of the 79 blocks, respectively. Cultured specimens were positive in about 10% of 79 biopsy specimens. CONCLUSIONS: Histological evidence of mycobacterial disease was only found in three quarters of patients that were clinically diagnosed and started on empirical treatment for tuberculous adenitis. Neither histological nor mycobacteriological evidence was found in a quarter of the patients who were already on treatment for TB, basing on clinical criteria. These findings call for new research on simple diagnostic tools for patients who seek care for s ymptoms of extra-pulmonary TB.

Reduced apoptosis and increased inflammatory cytokines in granulomas caused by tuberculous compared to non-tuberculous mycobacteria: role of MPT64 antigen in apoptosis and immune response.

Inhibition of apoptosis of infected macrophages by pathogenic mycobacteria is suggested to be an important virulence mechanism, but little is known about the mycobacterial proteins involved in the inhibition of apoptosis. In this study we investigated differences in apoptosis and immune response and their correlation with the expression of Mycobacterium tuberculosis complex-specific secretory protein MPT64 in lesions caused by tuberculous or non-tuberculous mycobacteria by analysing the in situ expression of apoptosis-related proteins (FasL, Fas, Bax, Bcl-2), apoptotic cells, inflammatory cytokines [tumour necrosis factor (TNF)-alpha, interleukin (IL)-10, transforming growth factor (TGF)-beta, interferon (IFN)-gamma] and MPT64 antigen. The discrimination of mycobacteria was made by nested polymerase chain reaction (PCR) amplification of IS6110, which is specific for M. tuberculosis complex organisms. Forty-seven cases of lymphadenitis with necrotic granulomas were evaluated. With nested PCR, 30/47 cases were positive for M. tuberculosis. MPT64 antigen was detected specifically in the PCR-positive cases. Granulomas caused by tuberculous mycobacteria had fewer apoptotic cells, higher numbers of cells expressing TNF-alpha and TGF-beta and less extensive necrosis than granulomas caused by non-tuberculous mycobacteria. There was a significant negative correlation between apoptotic cells and the number of cells expressing MPT64 antigens, suggesting a role for MPT64 protein in the inhibition of apoptosis. Granulomas with higher amounts of MPT64 also showed a greater number of cells expressing TGF-beta than those with lower amounts of MPT64. In conclusion, this study supports the hypothesis that inhibition of apoptosis is a virulence mechanism for tuberculous mycobacteria. Correlation of MPT64 antigen with expression of macrophage deactivating cytokines and reduced apoptosis suggests its role in pathogenesis and bacillary persistence.

Patient knowledge, practices and challenges to health care system in early diagnosis of mycobacterial adenitis.

OBJECTIVE: To assess diagnostic delay, knowledge and practices related to tuberculosis among patients with mycobacterial adenitis. DESIGN: A cross sectional study involving comparison analysis of high-risk groups. SETTING: Seven hospitals in rural and semi-rural districts of Arusha. SUBJECTS: Four hundred and twenty six clinically diagnosed adenitis patients. INTERVENTIONS: Biopsy specimens were processed for culture, histology, and sera for HIV testing. A questionnaire was used to assess knowledge, practice, and diagnostic time. MAIN OUTCOME MEASURES: Tribal comparisons were made using proportions and means. RESULTS: About 90% (387/423) of patients first visited medical facilities within a mean time of 10.1(SD, 15.7) weeks after becoming aware of their illness, and a diagnosis was made at a mean of 27 (SD, 25) weeks. Non-Iraqw patients, especially the Datoga, practised drinking raw milk (35.2% 43/122), eating raw animal products (18.8% 24/128) and living in houses with poor ventilation (33.6% 44/131), more than Iraqw patients. Of the investigations done, 14.5% (60/415) were culture positive, 11.3% (16/142) were HIV positive, and 73.6% (128/174) had histological features consistent with tuberculosis. The knowledge of TB spread by air droplets was poorer in Iraqw (74.1%, 203/274) than in non-lraqw (61.1%, 77/126) patients. About 35.0% (45/129) of non-lraqw and 27.3% (79/289) of Iraqw patients were not aware that TB could be transmitted from animals to humans. CONCLUSIONS: The health system diagnostic delay is about twice the patient delay. The knowledge and practices related to both human and bovine TB transmission were poor in all patients, especially in the patients from nomadic tribes.

Tuberculosis treatment outcome and health services: a comparison of displaced and settled population groups in Khartoum, Sudan.

SETTING: The Sudan National Tuberculosis Programme serves internally displaced and settled populations in Khartoum, Sudan. OBJECTIVES: To investigate whether treatment in the camps is satisfactory compared to the settled population and to World Health Organization (WHO) standards, and to map certain characteristics of the clinics that may explain differences in treatment outcome. DESIGN: A register analysis was done on sputum smear-positive and retreatment tuberculosis patients registered consecutively in the first and second quarters of 2000. The nine health facilities from which the patients were selected were investigated using a questionnaire. State tuberculosis officers were interviewed about regional treatment policies. RESULTS: Two hundred and ninety-five internally displaced and 154 settled patients from respectively five and four clinics were included. The cure and completion rates among new sputum smear-positive cases were significantly higher among displaced (65% and 9.3%) than among settled persons (43.5% and 21%). Displaced groups had better adherence to 5 and 8 month smear examinations, and the quantity of health education was higher in the camps than among the settled population. CONCLUSION: Tuberculosis treatment among the displaced population in Khartoum compares favourably with the neighbouring settled population, but both groups still face serious challenges to fulfil the WHO goals.

Effectiveness of community-based directly observed treatment for tuberculosis in an urban setting in Tanzania: a randomised controlled trial.

SETTING: An urban district in Dar es Salaam city with a high tuberculosis (TB) caseload. OBJECTIVE: To evaluate the effectiveness of community-based direct observation of treatment (DOT) using guardians and former TB patients compared to hospital-based DOT in an urban setting in Tanzania. DESIGN: Unblinded randomised control trial conducted in five sites under operational conditions in Temeke district. No changes to existing treatment delivery were made other than randomisation. The main outcome measure was treatment success. Analysis was by intention to treat. FINDINGS: A total of 587 new tuberculosis patients were enrolled. Among enrolled patients, 260 were assigned to community-based DOT using guardians and former TB patients and 327 to health facility-based DOT. Both DOT options gave similar treatment outcomes. Treatment success rate among patients under community and health facility-based DOT were 85% and 83%, respectively (OR 1.17, 95%CI 0.75-1.83). CONCLUSION: Community-based DOT is as effective as health facility-based DOT and can achieve good treatment outcomes, even in countries with well functioning National Tuberculosis Programmes.

Mycobacterial adenitis: role of Mycobacterium bovis, non-tuberculous mycobacteria, HIV infection, and risk factors in Arusha, Tanzania.

OBJECTIVE: To assess risk factors and mycobacterial agents in mycobacterial adenitis. DESIGN: Cross sectional involving comparison analysis of high-risk groups. SETTING: Seven hospitals in rural and semi-rural districts of Arusha. SUBJECTS: The study comprised of 457 patients of clinically diagnosed mycobacterial adenitis. INTERVENTIONS: Biopsy materials were cultured and identification of mycobacterial isolates, and HIV infection testing were performed using standard methods. A questionnaire was used to establish information for assessing risk factors. MAIN OUTCOME MEASURES: Proportions of mycobacterial isolates, risk factors and odds ratios. RESULTS: Of the 457 specimens, 65(14.2%) were culture positive. Isolates identified were M. bovis, 7(10.8%) M. tuberculosis, 27(41.5%) and non-tuberculous mycobacteria 31(47.7%). HIV infection and ingestion of raw milk were linked with increased risk of M. bovis infection by OR of 13.6 (95% CI, 1.7 - 109.9) and 15.28 (3.26 - 71.7), respectively. On multivariate analysis, an OR of 16.2 (1.3 - 201.3) for having M. bovis adenitis was linked to HIV infection, raw milk and houses with poor ventilation. An OR of 5.2 (1.2 - 20.6) for non-tuberculous mycobacterial adenitis was linked to history of TB in the family, HIV infection, raw milk, raw animal products and poor knowledge on transmission of tuberculosis. CONCLUSIONS: M. bovis caused one out of ten cases of culture positive mycobacterial adenitis. Non-tuberculous mycobacteria were more common than M. tuberculosis (50% and 40% of the cases, respectively). HIV infection and raw animal products are among the risk factors identified for M. bovis and non-tuberculous mycobacterial adenitis.

Tribal differences in perception of tuberculosis: a possible role in tuberculosis control in Arusha, Tanzania.

SETTING: Arusha, Tanzania. OBJECTIVE: To determine tribal differences in knowledge and practices that might influence tuberculosis control. METHOD: Twenty-seven villages were selected randomly out of 242 villages in four districts. In each village, a general and a livestock keeping group were selected at random. The households were home-visited and 426 family members were interviewed. RESULTS: On average, 40% of respondents practised habits that might expose them to both bovine and human tuberculosis. The Barabaig tribe had a significantly higher number of respondents (50%, chi2(2) = 5.1, P = 0.024) who did not boil milk. Eating uncooked meat or meat products was practised by 17.9% of all respondents. The habit was practised more by Iraqw (21.1%, chi2(2) = 6.9, P = 0.008) and Barabaig (31.6%, chi2(2) = 5.6, P = 0.016) than other tribes. About 75% of the respondents had a poor knowledge of tuberculosis. CONCLUSION: All tribes had habits and beliefs that might expose them to both bovine and human tuberculosis. The Iraqw and Barabaig tribes practised such habits more than other tribes. Knowledge of tuberculosis was limited in all tribes.

The role of livestock keeping in tuberculosis trends in Arusha, Tanzania.

SETTING: Arusha, Tanzania. OBJECTIVE: To assess risk factors that might influence TB control in the general population and in livestock-keepers. METHODS: Of 242 villages in four districts, 27 were selected randomly. In each village, a general and a livestock-keeping group were selected at random. The households were home-visited and 426 family members were interviewed. RESULTS: On average, three-quarters of households practised at least one risk activity for transmission of zoonotic tuberculosis, and respondents had poor knowledge about tuberculosis. In the livestock-keeping group, the risks of having a tuberculosis patient in the family were determined by poor ventilation (OR 2.6, 95% CI 1.1-6.5), confining livestock indoors with people (OR 2.3, 95%CI 1.1-5.0) and multiple determinants including poor ventilation (OR 13.5, 95% CI 2.5-71.7). Risk activities and the risks of having a tuberculosis patient in a family were significantly higher in the livestock-keeping group. CONCLUSIONS: The respondents had limited knowledge about tuberculosis, and the households had practices that posed potential risks for both human and bovine tuberculosis infection. Poor ventilation and confining livestock indoors were associated with tuberculosis spread in the households. These risks were observed more in the livestock-keeping group than in the general population group.

Risk of over-diagnosis of COPD in asymptomatic elderly never-smokers.

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) has defined stage I chronic obstructive pulmonary disease (COPD) as forced expiratory volume in one second/forced vital capacity (FEV1/FVC)% <70% and a FEV1% predicted of >80%. Stage 2 has been defined as FEV1/FVC <70% and a FEV1% pred of <80%. The authors examined the extent of COPD misdiagnosis using this definition in healthy, never-smoker, asymptomatic adults aged >70 yrs in Bergen, Norway. A respiratory questionnaire was mailed to a random sample of 2,871 persons aged >70 yrs. In a random, well-defined subgroup of 208 never-smoker respondents with no current respiratory disease and significant dyspnoea or heart disease/hypertension complicated with dyspnoea, 71 were able to perform an acceptable spirometry. Approximately 35% of these healthy, elderly never-smokers had an FEV1/FVC% of <70% and would be classified as having at least a stage 1 COPD. This percentage increased with age and in those aged >80 yrs approximately 50% would be classified as having COPD and approximately one-third would have an FEV1 of <80% pred (stage 2 COPD). The estimated 5th percentile of FEV1 was consistently <80% pred. The Global Initiative for Chronic Obstructive Lung Disease criteria will probably lead to a significant degree of over-diagnosis of chronic obstructive pulmonary disease in those aged >70 yrs. The criteria used to define the various stages of chronic obstructive pulmonary disease need to be age-specific.

[Immediate drug therapy of obstructive lung disease in hospital]. / Medikamentell straksbehandling i sykehus ved obstruktiv lungesykdom.

BACKGROUND: We have studied how patients with obstructive lung disease are treated in Norwegian hospitals and whether the treatment is in accordance with international guidelines. MATERIAL AND METHODS: During 76 days from 1 April 1997 we registered all 176 patients (110 women) admitted for obstructive lung disease in two hospital catchment areas in western Norway. The medical treatment given the first three hours after admission was recorded by the doctors on call. RESULTS: 106 patients (60%) were above 65 years of age; 21 (12%) below 35.31% of the patients had a mild form of the disease, 42% a moderate, 21% a severe, and 6% a life-threatening condition. Almost all patients with moderate and severe disease were treated with beta 2 agonists on admission. Among the patients with moderate disease, 25% did not receive glucocorticoids during the first three hours in hospital. The proportion of patients treated with theophylline was lower among those with mild disease than among those with moderate disease (15% and 65% respectively). INTERPRETATION: Guidelines are followed to a high degree in patients with severe or life threatening obstructive lung disease, but only party in those with mild or moderate disease.

Knowledge of disease and treatment among tuberculosis patients in Mwanza, Tanzania.

SETTING: A health care facility based study in a rural and urban setting in Mwanza region, Tanzania. OBJECTIVE: To determine patients' general knowledge of tuberculosis (TB) and the management of the disease. DESIGN: From 7 May to 7 July 1998, 296 pulmonary tuberculosis patients were consecutively interviewed. The majority of the respondents (89%) were outpatients. Questions were based on Tanzanian National Tuberculosis Programme (NTP) treatment guidelines for teaching tuberculosis patients. RESULTS: When correct answers to five out of seven questions asked was regarded as satisfactory knowledge, only 30% of the study population had satisfactory knowledge of disease and treatment. Persons with information on TB prior to diagnosis and those with higher education were more likely to have satisfactory knowledge (OR 9.23 and 19.93; 95%CI 2.77-31.08 and 5.74-69.19, respectively). There was a negative correlation between the level of knowledge and patients' age (-r = 0.181, P = 0.01). Knowledge was not significantly affected by sex or area of residence. The two most important sources of information about TB were health workers and former TB patients. CONCLUSIONS: Using NTP guidelines as reference, a substantial number of patients interviewed in health facilities in the study period had an unsatisfactory knowledge of TB disease and its management. The study did identify factors associated with satisfactory knowledge that could assist in designing health education intervention strategies.

Delay in tuberculosis case-finding and treatment in Mwanza, Tanzania.

SETTING: Health facilities in Mwanza region, Tanzania. OBJECTIVE: To determine factors responsible for delay from onset of symptoms of pulmonary tuberculosis to initiation of treatment. DESIGN: A cross-sectional descriptive study of 296 smear-positive tuberculosis patients. Emphasis was given to periods between 1) onset of symptoms and first consultation to a health facility, and 2) reporting to a health facility and initiation of treatment. RESULTS: Mean total delay was 185 days (median 136), with nearly 90% of this being patient's delay. The mean health system delay was 23 days (median 15), with longer delays in rural health facilities. The mean patient's delay was 162 days (median 120). This delay was significantly longer in rural areas, for patients with lower level of education, for those who first visited a traditional healer, and for patients who had no information on tuberculosis prior to diagnosis. Only 15% of the patients reported to a health facility within 30 days of onset of symptoms. CONCLUSION: There are significant delays in case-finding in Mwanza, Tanzania, with prolonged patient's delay. Facilitation of utilisation of health services, raising awareness of the disease and incorporation of private practice into tuberculosis control could help to reduce these delays.

[Hospital admissions due to obstructive lung diseases and pneumonia in two hospital districts]. / Innleggelser for obstruktiv lungesykdom og pneumoni i to sykehusområder.

Admission rates for specific diseases in a defined district can be used as a coarse estimate of the need for health services. Such registration has not previously been conducted in the hospital districts of Bergen and Haugesund. We recorded all patients 16 years and older admitted to three hospitals for obstructive lung disease or pneumonia in the two hospital districts of Bergen and Haugesund in April to June 1997. A total of 438 patients were included in both districts, 246 with obstructive lung disease and 192 with pneumonia. The admission rate for obstructive lung disease was 359 per 100,000 inhabitants per year, for pneumonia 280 per 100,000 inhabitants per year. Median age was between 71 and 75 years for men and women for both diseases. 13% of patients with obstructive lung disease were readmitted to the hospital within 30 days. Obstructive lung disease and pneumonia are common causes of hospital admission, especially among older persons. The admission rates for both diseases combined were 639 per 100,000 adults per year in the hospital districts of Bergen and Haugesund.

[Diagnosis and treatment of obstructive lung diseases]. / Diagnostikk og behandling av obstruktive lungesykdommer.

Obstructive pulmonary disease can be divided into bronchial asthma and chronic obstructive pulmonary disease. Using a questionnaire, we carried out a survey among doctors in Hordaland county in order to discover how they diagnosed and treated obstructive pulmonary disease. The response rate was 60%; 119 general practitioners and 48 hospital doctors. In spite of recommended guidelines, 20% of the doctors did not perform any kind of spirometry when diagnosing obstructive pulmonary disease. Spirometry after inhalation of bronchodilators or corticosteroids was performed by 29% of the doctors when diagnosing chronic obstructive pulmonary disease and by 43% when diagnosing asthma. 88% of the doctors who participated in our survey preferred to treat asthma with inhalation of beta-agonist or inhalation of corticosteroids, or both. This was in accordance with recommended guidelines. There was greater uncertainty amongst the doctors concerning the treating of chronic obstructive pulmonary disease, and the guidelines were followed to a lesser extent.

Prognostic significance of p53 protein expression and DNA ploidy in surgically treated non-small cell lung carcinomas.

A series of 112 patients operated for non-small cell lung cancer was analyzed retrospectively. Nuclear suspensions were prepared from formalin-fixed, paraffin-embedded biopsies, and DNA content was measured simultaneously with p53 expression using flow cytometry. The expression of p53 protein was determined by the monoclonal antibody PAb 1801, which recognizes both wild-type (normal) and mutated forms of p53. By the level of p53 expression, four patient groups were statistically defined. Patients in the two groups with no detectable and extremely high p53 expression had a significantly better prognosis than patients in the two groups with moderately increased p53 expression. By logistic regression, p53 expression was found to be the single best predictor of 5 year survival. Patient age and tumor stage were less important prognostic factors. No difference in 5 year survival was observed between diploid and aneuploid tumors. We conclude that p53 is a useful prognostic predictor in low stage non-small cell lung carcinoma using the monoclonal antibody PAb 1801. The applicability of this antibody to archival material in flow cytometric analysis should allow a broad range of tumor types to be analyzed with respect to the prognostic significance of p53 overexpression.

Quantitation of biological tumor markers (p53, c-myc, Ki-67 and DNA ploidy) by multiparameter flow cytometry in non-small-cell lung cancer.

Fifteen primary non-small-cell lung carcinomas (8 adenocarcinomas and 7 squamous-cell carcinomas) were analyzed by multiparameter flow cytometry for their expression of p53 and c-myc proteins. In addition, the fraction of cells staining with the proliferation-associated antibody Ki-67 and DNA ploidy was determined. These 4 biological markers were analyzed in parallel samples from a single-cell suspension made from fresh, frozen biopsies. Thus, the internal relationship between these markers within each tumor-cell population was established. Three different anti-p53 antibodies were used: PAb 421, PAb 1801 and PAb 240. All 15 tumors were p53-positive with the antibodies PAb 1801 and PAb 240, whereas only 9 were positive as judged by the antibody PAb 421. This indicates that the choice of p53 antibody is not irrelevant. Ten tumors were c-myc-positive; 7 of these were adenocarcinomas. The c-myc-positive tumors had a significantly higher level of p53 expression, judged by PAb 1801 and PAb 240, than c-myc-negative tumors. For PAb 421, there was no difference. We did not find any correlation between Ki-67 staining and expression of p53 and c-myc proteins, either with DNA ploidy, S-phase fraction or histological type. Our study indicates that there might be an association between accumulation of p53 protein and c-myc over-expression in non-small-cell lung cancer, and that this in particular might apply to adenocarcinomas. Furthermore, we show that multiparameter flow cytometry is a powerful tool in the study of the relationship between different markers in a cell population.

Expression of p53 protein in cutaneous melanoma.

The purpose of the present study was to examine the expression of p53 protein in malignant melanomas of the nodular sub-type, with special reference to the role of p53 alterations in the development of metastases. Increased expression of p53 protein was found in 29 of 30 cases using PAb1801 monoclonal antibody (MAb) and flow-cytometric detection on archival material. A large proportion of the cells were positive in a majority of the cases. The level of expression was not correlated to DNA ploidy or to subsequent development of local metastases. However, a significant decrease in p53 protein expression was observed in metastatic lesions, as compared with the corresponding primary tumors. Our results indicate that p53 alterations may be an early event in melanoma development, since almost all cases were affected, and that metastatic spread appears to be parallelled by decreased p53 protein expression.