Outbreak of tuberculosis in a closed setting: views on transmission based on results from molecular and conventional methods.

BACKGROUND: This study describes an outbreak of tuberculosis (TB) in a nursing home for men with mental disorders where residency is lengthy or permanent. This type of setting can provide a model of transmission as contact with the rest of society is extremely limited. AIM: To determine if cases of TB, diagnosed around the same time and in the same place, are linked based on results using molecular and conventional methods. METHODS: The strains of Mycobacterium tuberculosis were analysed by drug resistance testing and mycobacterial interspersed repetitive units-variable number tandem repeats (MIRU-VNTRV). Microbiological results were related to clinical history and time of diagnosis. FINDINGS: Nine patients were diagnosed with TB, and strains were recovered from seven of these patients. Unexpectedly, the strains with the same genotype showed different patterns of resistance, and only two strains demonstrated identical patterns. MIRU-VNTR analysis demonstrated that one patient was infected with two different strains. CONCLUSION: Variation between the strains indicates that the outbreak may have arisen from several sources of infection. The variation in resistance indicates that rapid emergence of antimicrobial resistance is possible. As such, several questions are raised concerning source of infection, development of disease, resistance and mixed infections.

Tuberculin skin test reactivity of health care students in a country with a low prevalence of tuberculosis.

SETTING: Health care students in Sweden. OBJECTIVE: To analyse the distribution of tuberculin skin test (TST) reactions and epidemiological factors related to TST reactivity. DESIGN: TST reactivity was analysed in 1190 students. A linear regression model was created for the relative contribution of background factors of TST reactivity. A subgroup of 287 non-vaccinated subjects was comparatively skin-tested with Mycobacterium avium sensitin and tuberculin. RESULTS: Among non-bacille Calmette-Guérin (BCG) vaccinated students, 91% had no TST reaction (0 mm induration) and reactions of ≥ 10 mm were found in 2.9%, whereas 34% of BCG-vaccinated students had no TST reaction and 42% had reactions of ≥ 10 mm. The expected contribution to TST reactivity was 6.0 mm for a history of BCG vaccination, 3.0 mm for a country of birth with medium/high incidence of TB and 1.6 mm per 10 years of age. The sensitin reactions exceeded the TST reactions by ≥ 3 mm in 52% of the comparatively tested subjects with TST reactions of ≥ 1 mm. CONCLUSION: BCG vaccination, cross-reactivity with non-tuberculous mycobacteria, geographic origin and age had a decisive influence on TST reactivity. Most non-vaccinated health care students were non-reactive, which highlights the need to organise preventive measures in settings where TB exposure is expected.

The tuberculin skin test in relation to immunological in vitro reactions in BCG-vaccinated healthcare workers.

The aim was to study the tuberculin skin test in relation to immunological in vitro reactions in bacille Calmette-Guerin (BCG)-vaccinated healthcare workers. The present study was performed in Sweden, a country with a low incidence of tuberculosis, a high BCG vaccination efficacy and high tuberculin conversion rates. BCG-vaccinated healthcare workers (n=381) were tuberculin skin tested. From these, 11 subjects with negative tuberculin reactions (<6 mm) were matched for age and sex with 11 subjects with large positive reactions (> or = 15 mm). Lymphocyte transformation and the production of interferon-gamma (IFN-gamma) were analysed after stimulation in vitro of peripheral blood mononuclear cells with tuberculin purified protein derivative, heat-killed tubercle bacilli and a culture filtrate from tubercle bacilli. In the tuberculin-positive group the lymphocyte transformation response was 2-3 times larger, and IFN-gamma production was 7-10 times larger, than in the tuberculin-negative group (p<0.001). The present results suggest that a positive tuberculin skin test in bacille Calmette-Guerin-vaccinated subjects indicates a stronger immune response of the protective T-helper 1-type than does a negative test. In similar settings, the study supports the traditional practice of regarding the tuberculin skin test in bacille Calmette-Guerin-vaccinated subjects as an indicator of a protective immune response against tuberculosis.

[Tuberculosis a threat again. Multiresistance in the Baltic States and in Russia; Nordic countries initiate cooperation to prevent transmission]. / Tuberkulos åter ett hot. Multiresistens i Baltikum och Ryssland; nordiskt samarbete inlett för att hejda spridning.

The incidence of tuberculosis (TB) has more than doubled in the Baltic States during the last decade and is now 10-15 times higher than in Sweden. It is also a serious problem in Russia. Strains resistant to one or several of the anti-tuberculous drugs are common as is multi-drug resistance (MDR), i.e. strains resistant to the two most effective drugs rifampicin and isoniazid. MDR-TB is very difficult to treat; the mortality rate is high. Initiatives have been taken in the Nordic countries in order to help to control and improve the situation by way of supportive measures.

[Shortages in Swedish tuberculosis care. Good results only in 71 percent of cases after 12-month treatment as shown in a current study]. / Det finns brister inom den svenska tuberkulosvården. Fullgott resultat efter tolv månader hos endast 71 procent visar aktuell studie.

During the period August 1994-December 1995 783 cases of active tuberculos (TB) were notified to the health authorities in Sweden. By means of questionnaires sent to the consulting physicians (92 per cent response rate) the treatment outcome was studied twelve months after the diagnosis. Out of 676 patients only 71 per cent were reported to have completed the treatment and be cured of TB. This indicates that there is room for improvement as regards monitoring patients, if necessary by Directly Observed Therapy (DOT), in order to make sure that prescribed treatment is adhered to.

Therapeutic drug monitoring in patients with cystic fibrosis and mycobacterial disease.

Cystic fibrosis (CF) patients require higher dosages of many antibiotics. The relapse of tuberculosis in one CF patient, and the repeated growth of Mycobacterium avium-intracellulare in another, despite conventional therapy, raised the question of whether the serum levels of the antimycobacterial drugs were adequate. Antimycobacterial drug serum concentrations were assayed in 10 CF patients with pulmonary mycobacterial disease. Serum levels below the proposed target range were seen 2 h after drug intake in the initial four patients treated: for rifampicin in 2/3, ethambutol in 3/4 and for clarithromycin in 2/3 patients, despite standard dosages. Reassays after dose adjustment and assays in six other patients showed that adequate levels were not achieved 4 h after clarithromycin in 3/5, ethambutol in 1/5, ciproflaxacin in 1/2 and ofloxacin in 2/2 patients. The patient with relapse of tuberculosis and the patient with continuous growth of M. avium-intracellulare improved and became culture negative after dose adjustment. Low drug serum levels is one reason for therapy failure in cystic fibrosis patients with mycobacterial disease. Therapeutic drug monitoring is recommended.

Prevalence of allergy in children in relation to prior BCG vaccination and infection with atypical mycobacteria.

By influence on the Th1/Th2 cell balance, infectious agents may affect the development of atopic allergy. In this study, we investigated whether previous BCG vaccination or infection with atypical mycobacteria might be related to the development of atopic disease. The study, which involved skin testing with mycobacteria and answers to a questionnaire for more than 6000 children in Sweden, revealed a low prevalence of allergy among BCG-vaccinated children who were immigrants or adopted from other countries. Vaccinated children born in Sweden, however, did not have significantly lower allergy prevalence than age-matched, unvaccinated children. Furthermore, the overall frequencies of skin-test reactivity to the atypical mycobacteria M. avium and M. scrofulaceum were higher rather than lower in allergic than in nonallergic children. By contrast, there was a tendency toward a lower frequency of more strongly positive skin reactions (> or = 10 mm) to mycobacteria in allergic than in nonallergic children. These findings do not support the hypothesis that early mycobacterial infections have a suppressive effect on the development of atopic disease. Earlier findings of an apparent association between atopy and lack of previous mycobacterial infection may possibly be explained by a relatively decreased ability of atopic patients to mount strong Th1 cell-mediated immune responses.

[Policy program to minimize spread of infection. Prolonged cough may be a sign of tuberculosis]. / Policyprogram för minskad smittspridning. Långdragen hosta kan vara tuberkulos.

In a worldwide epidemiological perspective, Sweden is well favoured with an annual tuberculosis incidence of approximately six cases per 100,000 of the population. Neither the impact of the HIV pandemic nor the occurrence of multiresistant strains of Mycobacterium tuberculosis has yet become a major problem in the care of tuberculosis patients in Sweden. Only a few per cent of HIV patients have developed tuberculosis, and during the period, 1991-94, only one per cent of M. tuberculosis isolates in Sweden were resistant to such antimycobacterials as isoniazid and rifampicin. However, the epidemiological situation in the neighbouring Baltic states is a matter for concern. Bovine tuberculosis has been eradicated in Sweden, the last case having been diagnosed in 1978. Although the reported efficacy of BCG (bacillus Calmette-Guérin) tuberculosis vaccine varies according to the population studied, protective rates of 70-85 per cent have been reported for Sweden and other west European countries. Re-vaccination of tuberculin-negative individuals has not been shown to yield added protection. The aim of a national programme for protection against tuberculosis is to preserve our favourable epidemiological situation by early detection of new cases, effective contact tracing, and BCG vaccination of children in population groups at risk. The primary means of achieving this is the education of health care personnel to retain tuberculosis as a differential diagnosis. Moreover, national guidelines for contact tracing must be duly observed, and immigrants from high prevalence areas need to be screened for tuberculosis. Registration of all cases of tuberculosis should be maintained at regional and national levels, and follow-up must be meticulous until a successful outcome of treatment is accomplished. Recommendations for dealing with tuberculosis should be made available and duly implemented at all hospitals caring for tuberculosis patients, in order to avoid nosocomial transmission. Although BCG vaccination at birth was formerly general in Sweden, since 1975 only children considered to be at risk have been vaccinated. Thus, non-vaccinated young adults are now entering the health care sector as students or employees, and should be offered BCG vaccination. Moreover, the epidemiological situation both in Sweden and in neighbouring countries needs to be monitored carefully in order that recommendations concerning BCG vaccination and other preventive measures can be modified if necessary.

Temporary intrathoracic adenopathy in children--a response to infection caused by non-tuberculous mycobacteria?

Two children, 4 and 8 years old, were skin tested with sensitins and found to have indurations of 20 mm. Sensitins are tuberculins deriving from non-tuberculous mycobacteria. The children showed pathological enlargement of mediastinum on chest radiography. They were further examined, and no findings supported malignancy nor tuberculosis. The chest radiographs were normalizing within a few months. The large sensitin reactions together with the other findings indicate that the children had been infected with non-tuberculous mycobacteria.

Palpable lymph nodes of the neck in Swedish schoolchildren.

We studied 3592 Swedish schoolchildren, 8 or 9 years old, examined for palpable submandibular, cervical and supraclavicular lymph nodes. All children were skin tested with 2 TU PPD RT23 and with 0.1 microgram of Mycobacterium avium sensitin or 0.1 microgram of M. scrofulaceum sensitin. A total of 991 children had palpable lymph nodes in any of the three locations. Among them, 811 had lymph nodes in one location, 162 in two locations and 18 in three. In 312 children, the lymph nodes were > or = 5 mm in size in any location. The most common location was submandibular. Boys had a significantly higher prevalence of palpable lymph nodes than girls. There was also seasonal variation. Children infected by atypical mycobacteria (sensitin reaction > or = 6 mm) did not have a higher prevalence of palpable lymph nodes than those not infected.

Sensitivity to sensitins and tuberculin in Swedish children. Part 5: A study of school children in an inland rural area.

SETTING: Since 1986 we have tested approximately 7000 non-BCG-vaccinated Swedish children with tuberculin and with Mycobacterium avium or M. scrofulaceum sensitin. In Göteborg, an urban coastal area, 25% of 8-9-year-old school children reacted to M. avium sensitin and 32% of M. scrofulaceum sensitin using a 6 mm cut-off. OBJECTIVE: To evaluate if geographical factors have an influence on the prevalence of children reacting to tuberculin and sensitins. DESIGN: 2000 schoolchildren of the same age as those in Göteborg but living in an inland rural area were Mantoux-tested in a similar way (simultaneously on separate arms with PPD RT23 and either of the two sensitins). RESULTS: 15% reacted to PPD RT23, 9.7% to M. avium and 13.9% to M. scrofulaceum sensitin. None of the children with a PPD RT23 reaction > = 6 mm showed signs of tuberculosis or had any known exposure. A reaction to PPD RT23 was usually combined with a still larger sensitin reaction. CONCLUSION: There was a considerable geographic difference in sensitin reactivity, low in an inland rural area compared to a coastal urban area. Children reacting to PPD RT23 had probably not been infected by M. tuberculosis but more likely by atypical mycobacteria. The reactions should be interpreted as cross-reactions.

Protein intake and glomerular hyperfiltration in insulin--treated diabetics without manifest nephropathy.

Protein intake in relation to glomerular filtration rate (GFR) and urinary albumin excretion (UAE) has been studied in 96 insulin-treated diabetic patients, 20-40 years of age and without nephropathy. They had diastolic blood pressure (DBP) not exceeding 90 mmHg and a GFR exceeding -2 SD of the age-related value. They were without medications except for insulin. There were no significant differences in protein intake between diabetic patients with and without hyperfiltration (1.18 +/- 0.26 g/kg/d vs 1.21 +/- 0.42 g/kg/d, p = 0.75) or between diabetic patients with or without increased UAE (1.16 +/- 0.41 g/kg/d vs 1.24 +/- 0.37 g/kg/d, p = 0.37). No relations were found between protein intake and GFR or UAE in the whole sample, but a positive relation was found between UAE and protein intake in patients with increased UAE. Protein intake correlated with UAE in hyperfiltrators who use tobacco (n = 8, r = 0.85, p = 0.01), but not in non-users (n = 11, r = 0.24, p = 0.48). In conclusion our findings give no support for a relation between high protein intake and glomerular hyperfiltration in insulin-treated-diabetic patients. However, in contrast to non-users of tobacco, a positive relation was found between UAE and protein intake in tobacco users with hyperfiltration.

Sensitivity to sensitins and tuberculin in Swedish children. IV. The influence of BCG-vaccination.

BCG-vaccinated schoolchildren, 8-9 yrs of age, were simultaneously tested on separate arms with tuberculin and a sensitin. Using the 6 mm cut-off they reacted in 49% to two tuberculin units purified protein derivative (PPD RT23), in 67% to 0.1 micrograms Mycobacterium avium sensitin RS10, and in 58% to 0.1 micrograms M. scrofulaceum sensitin RS95. The corresponding figures for non-BCG-vaccinated schoolchildren of the same age tested at the same time were 3, 25 and 32%, respectively. The results indicate a stimulating influence of BCG-vaccination on tuberculin and sensitin reactivity. Since the sensitin reactions were the larger ones, these reactions were not only due to the vaccination. The BCG-vaccinated schoolchildren seem to have acquired infections by atypical mycobacteria despite vaccination.

Cigarette smoking and urinary albumin excretion in insulin-treated diabetics without manifest nephropathy.

The frequency of microalbuminuria and glomerular hyperfiltration in insulin-treated diabetics without manifest nephropathy was studied in 76 patients, 20-40 years of age and with a diabetes duration not exceeding 20 years. Clinical determinants of urinary albumin excretion (UAE) with regard to smoking were studied further in a sample of male diabetics (n = 49) without manifest nephropathy. All patients had an age-related glomerular filtration rate (GFR) exceeding -2 SD, and their diastolic blood pressure (DBP) did not exceed 90 mmHg. GFR was assessed by 51Cr-EDTA-clearance, and UAE was analysed using an immunochemical method. Diabetic smokers with a long diabetes duration (10-20 years) had a significantly higher UAE (39.5 +/- 2.4 mg 24 h-1 vs. 17.1 +/- 2.4 mg 24 h-1; P = 0.03), a higher mean arterial blood pressure (MAP) (97.9 +/- 7.5 mmHg vs. 91.5 +/- 6.3 mmHg; P = 0.02) and a higher frequency of micro-albuminuria (85.7% vs. 37%; P = 0.028) than non-smoking diabetics. Smokers with a short diabetes duration (0-10 years) had a significantly higher frequency of glomerular hyperfiltration (64% vs. 15%; P = 0.005) than non-smokers. The frequency of microalbuminuria or blood pressure did not differ significantly. In male non-smokers (n = 35) UAE was positively correlated with HbAlc and negatively correlated with age of onset. In male smokers (n = 14) regression analysis showed that UAE was positively correlated only with duration of smoking. We conclude that smoking is associated with two accepted risk factors for nephropathy in insulin-treated diabetics, namely hyperfiltration and microalbuminuria. A positive linear relationship between smoking parameters and UAE in male diabetics also supports the view that smoking may increase the risk of nephropathy development in insulin-treated diabetics.

Sensitivity to sensitins and tuberculin in Swedish children. III. Sequential versus simultaneous skin testing.

The aim of this study was to determine whether simultaneous and sequential skin testing with tuberculin and sensitins give consistent results. A total of 475 8- or 9-year-old schoolchildren were skin tested sequentially, at an interval of 3 days, with PPD tuberculin and with either Mycobacterium scrofulaceum or M. avium sensitin. The results were compared with those of 470 simultaneously tested children chosen from the same living area. There were no statistically significant differences between the frequencies of the reactions of sequentially and simultaneously tested children. When the sequential testing procedure was employed, 3.1% reacted to tuberculin, 19% to M. avium sensitin and 30% to M. scrofulaceum sensitin, taking a 6 mm cut-off. The corresponding figures for the simultaneously tested children were 4.7, 21 and 36%, respectively. Thus, there was no indication that the simultaneous testing procedure in itself influenced the results, neither was there any sign of a booster effect when testing in sequence with an interval of 3 days in non-BCG-vaccinated children.

Sensitivity to sensitins and tuberculin in Swedish children. I. A study of schoolchildren in an urban area.

Non-BCG-vaccinated schoolchildren (8 or 9 years of age) were simultaneously tested on separate arms with 2 IU PPD RT23 and 0.1 microgram Mycobacterium avium sensitin RS10 or 0.1 microgram Mycobacterium scrofulaceum sensitin RS95. None of the 2819 analysed children had any known exposure to tuberculosis. A total of 3.4% reacted with an induration greater than or equal to 6 mm to PPD RT23. Half the number of children were tested with M. avium sensitin and 25.4% reacted while the remaining were tested with M. scrofulaceum sensitin and 32.4% reacted when the cut-off was 6 mm. For about 90% of the children the sensitin reaction was larger than or equal to the tuberculin (PPD RT23) reaction. Correlation analyses showed that moderate and high PPD RT23 values were combined with still higher sensitin values, indicating that the tuberculin reactions were mainly cross-reactions due to the antigenic similarity between tuberculin and sensitins. The presence of birds, dogs and cats in the homes was combined with an increased frequency of children reacting to the sensitins used. The children with reactions to PPD RT23 greater than or equal to 6 mm were examined and chest X-rays were performed. None of them showed any signs or symptoms of mycobacterial disease. In non-BCG-vaccinated Swedish schoolchildren without clinical signs of tuberculosis and without known contact with a contagious tuberculous person, indurations less than 12 to 14 mm on tuberculin testing are probably caused by atypical mycobacteria. In such cases sensitin tests should be performed to verify the suspicion.

Sensitivity to sensitins and tuberculin in Swedish children. II. A study of preschool children.

Non-BCG-vaccinated preschool children (4 or 5 years of age) were simultaneously tested on separate arms with a 2 IU PPD RT23 and 0.1 microgram Mycobacterium avium sensitin RS10 or 0.1 microgram Mycobacterium scrofulaceum sensitin RS95. None of the 762 children had any known exposure to tuberculosis. A total of 8.8% reacted with an induration (greater than or equal to 3 mm to PPD RT23 while 2% reacted with greater than or equal to 6 mm. Half the children were tested with M. avium sensitin: 18.9 and 7.8% reacted when 3 and 6 mm cut-off points, respectively, were taken. The remaining children were tested with M. scrofulaceum sensitin: 18.4 and 6.3%, respectively, reacted. In a previous study of schoolchildren aged 8 or 9 years, reactions to sensitins were considerably more frequent. Thus, sensitisation by atypical mycobacteria seems to increase from the preschool to the early school age. This finding probably reflects a continuous exposure of the children to atypical mycobacteria from various sources. The preschool children with a reaction to PPD RT23 greater than or equal to 6 mm were examined and chest X-rays were performed. All children were healthy but one child had enlarged lymph nodes in the mediastinum and abdomen. It cannot be excluded that these pathological findings were caused by atypical mycobacteria.

Cigarette smoking and glomerular filtration rate in insulin-treated diabetics without manifest nephropathy.

A sample of 120 insulin-treated diabetics, 20-40 years of age, with a glomerular filtration rate (GFR) exceeding -2 SD of the age-adjusted value and without albuminuria greater than 300 mg 24 h-1, and with a diastolic blood pressure not greater than 90 mmHg, were studied in order to evaluate the possible effect of smoking on glomerular filtration rate. The patients reported their smoking habits, use of oral snuff, use of alcohol, physical exercise and heredity for hypertension in a simple questionnaire. GFR was assessed with 51Cr-EDTA-clearance and glomerular hyperfiltration was defined as a value exceeding +2 SD of the age-adjusted normal value. We found a significantly higher prevalence of glomerular hyperfiltration in smokers than in non-smokers (41% vs. 18%), but no increased prevalence in users of oral snuff. In cigarette smokers a multivariate analysis revealed that GFR was positively related to body mass index (BMI), and negatively related to the number of cigarettes smoked per week and the mean blood pressure. In non-smokers GFR was dependent only on age. We conclude that in insulin-treated diabetics glomerular hyperfiltration is related to smoking, and that the GFR in smoking diabetics is directly dependent on the smoke doses. As glomerular hyperfiltration is regarded as a risk factor for diabetic nephropathy, our findings should be relevant to preventive measures in clinical work.