Unchanged acetylation of isoniazid by alcohol intake.

SETTING: In 10 healthy subjects, the influence of acute alcohol intake on the pharmacokinetics of isoniazid (INH) was studied. OBJECTIVE: To test the hypothesis that alcohol increases the conversion of INH by acetylation into its metabolite acetylisoniazid. DESIGN: In a crossover design, an oral dose of 300 mg INH was administered on 2 separate days, 14 days apart, with or without alcohol to a serum alcohol of about 21 mmol/l (1 g/l) maintained for 12 h. RESULTS: Neither the metabolism of INH nor that of acetylisoniazid was changed by acute alcohol intake. CONCLUSION: Acute alcohol intake has no impact on the conversion of INH to its metabolite acetylisoniazid, which is catalysed by the enzyme N-acetyltranferase. Accordingly, a metabolic effect of acute alcohol intake on INH metabolism probably contributes little to the therapeutic failure of anti-tuberculosis treatment among alcoholics.

Attitudes toward an unsolicited approach in relation to status of genetic disease: exemplified by alpha(1)-antitrypsin deficiency.

Knowledge of a genetic disease in an individual raises the questions of whether and how this information should be communicated to his or her family. The aim of the present study was to provide factual information about attitudes towards an unsolicited approach from a physician regarding genetic counseling within affected families. We performed a questionnaire study among patients with alpha(1)-antitrypsin deficiency, their examined and unexamined relatives, and a control group of Danish citizens. Of 2,146 subjects, the questionnaires were returned by 1,761 (82%), and 1,609 (75%) wanted to participate. Stepwise logistic regression showed that phenotype/subgroup, having descendants, and being female were significantly related to the approval of an unsolicited approach and the informing of relatives. Provided it was difficult for the index case to inform relatives about their risk and about his/her disease, then a total of 75.8% would not proscribe an unsolicited approach by the physician. Most of those for proscribing an unsolicited approach found that relatives should be informed in advance by the index case. The control group of randomly chosen Danes was the most skeptical towards an unsolicited approach. Most individuals found that genetic risk information should be shared with relatives at-risk. A flexible information policy by the health care system based on active approach towards relatives is acceptable to 75 to 95% of individuals in order to ensure diffusion of genetic risk information within families segregating for a genetic disease with a modifiable outcome.

Risk of hospital admission for obstructive pulmonary disease in alpha(1)-antitrypsin heterozygotes of phenotype PiMZ.

Whether subjects heterozygous for alpha(1)-antitrypsin (alpha(1)-AT) deficiency are at risk for development of obstructive pulmonary disease (OPD) has been discussed for the past three decades. Both cohort and case-control studies have reached different conclusions, with the major problems being small sample sizes. A cohort of heterozygotes with the phenotype PiMZ was retrieved from the Danish Alpha(1)-Antitrypsin Deficiency Registry. Ten matched controls for each PiMZ subject were identified from the files of the Danish Central Population Registry. Cases and controls were subsequently linked to the files of the Danish Hospital Discharge Registry, and relative risk for OPD was calculated. In the cohort of 1,551 PiMZ subjects (11,678 person-years), we identified 47 subjects with a discharge diagnosis of OPD, as compared with 206 subjects with this diagnosis in the control group (109,748 person-years), yielding a relative risk (RR) of 2.2 (95% confidence interval [CI]: 1.5 to 3.0). This increased risk was present in both men and women and in all age groups; however, it was significant only in the age group from 40 to 79 yr. Of the 1,551 PiMZ subjects, 565 (36%) were first-degree relatives of PiZ index cases, and it appeared that only this group was at increased risk of hospital admission for OPD (RR: 3.4, 95% CI: 2.2 to 5.3). We conclude that alpha(1)-AT heterozygotes of phenotype PiMZ are at increased risk of hospital admission for OPD if they are first-degree relatives of PiZ index cases only, and that other, yet unknown genetic or environmental factors contribute to the development of lung disease.

Transmitting genetic risk information in families: attitudes about disclosing the identity of relatives.

Attitudes about disclosing the identities of family members to a physician to ensure diffusion of genetic risk information within affected families were examined in a questionnaire study of Danish patients with alpha1-antitrypsin deficiency (A1AD), their relatives, and a control group of Danish citizens. The questionnaires were returned by 1,761 (82%) of 2,146 recipients; 1,609 (75%) agreed to participate and completed the questionnaire. Only 2.8% objected to disclosing the identity of children, 9.1% objected to disclosing the identity of parents, and 6.7% objected to disclosing the identity of siblings. When genetic tests are offered to a sister, 75.4% of screened individuals with severe A1AD (phenotype "piZ") and 66.8% of piZ probands thought that the physician should say who is ill. Important reasons for informing a sister at risk were, for 58%, the opportunity to prevent disease and, for 41% of piZ-probands, the opportunity to maintain openness in the family and to avoid uncertainty. Stepwise logistic regression of background variables showed that relatives were those for whom most respondents approved the disclosure of the parents' and siblings' identities to enable the physician to examine them for the presence of A1AD. Women were less prone to disclose the identity of siblings. The results indicate that the genetic counselor should inquire about relatives' identities, to ensure that they are properly informed about the known risk of severe genetic disorder, such as A1AD, for which disability can be prevented by a change of lifestyle or by careful management. Disease prevention is essential, but openness and avoidance of uncertainty in affected families are also important. Our findings imply that fully informing all relatives about the disorder and about who is actually ill should be the principal rule.

Salmeterol reduces the need for inhaled corticosteroid in steroid-dependent asthmatics.

Previous results have demonstrated addition of long-acting beta2-adrenergic agonists to be beneficial in asthma patients already receiving inhaled corticosteroid. The purpose of this study was to determine, qualitatively as well as quantitatively, the steroid-sparing properties of salmeterol in stable asthma patients receiving maintenance inhaled corticosteroids (800-1600 microg day(-1)). In these patients, the daily dose of beclomethasone dipropionate was reduced by 200 microg each week until asthma deteriorated, with the minimal acceptable dose (MAD) being defined as the dose one step above deterioration (sensitivity period). Following this, patients received three times the MAD for 2 weeks. Patients were randomized to receive either salmeterol 50 microg twice daily or placebo and the MAD was again determined (treatment period). Forced expiratory volume in 1 sec (FEV1) was measured each week. Morning and evening peak expiratory flow (PEF), symptom score and use of bronchodilator were recorded each day. Fifteen patients received salmeterol and 19 placebo. The MAD was significantly lower in the salmeterol group compared with placebo during the treatment period (P<0.01). A 50% reduction of the MAD was achieved by more patients treated with salmeterol than placebo (P = 0.001). Salmeterol caused a significantly greater reduction in daytime symptom score and use of as-needed beta2-agoinist therapy between sensitivity and treatment periods compared with placebo (P<0.05 for both). The results demonstrate, that the addition of salmeterol to corticosteroid treatment offers a clinically relevant potential for reduction of inhaled corticosteroid dose in steroid sensitive asthmatics.

Radiographic spectrum of adult pulmonary tuberculosis in a developed country.

SETTING: Bispebjerg Hospital, Department of Pulmonary Medicine P. The referral centre of adult tuberculosis in the municipality of Copenhagen, Denmark. OBJECTIVE: To evaluate the radiographic spectrum of pulmonary tuberculosis (TB) in adults in a low-prevalence country and to correlate radiographic appearances with bacteriological results, clinical and demographic data. DESIGN: Retrospective review of medical files on 548 cases with pulmonary TB according to the criteria of WHO. RESULTS: Usual radiographic pattern of reactivating TB, with upper lobe involvement, was found in 92% (n = 504), eight percent (n = 44) showed unusual X-ray patterns for adults, such as isolated lower lobe infiltrations (n = 19), hilar adenopathy (n = 10), miliary TB (n = 7), tuberculoma (n = 2), pleural effusion (n = 1) and normal chest X-ray (n = 3). Eight-nine percent of cases with cavitary lesions were positive by microscopy. CONCLUSION: The risk of missing a diagnosis of pulmonary TB may be high if patients present with an X-ray unusual for TB, but this is fortunately seen only in 8% of cases of pulmonary tuberculosis. Unusual X-ray is more commonly found in patients with concomitant disease, such as diabetes and cancer. If chest X-ray shows cavities, but the smear is negative for Mycobacterium, TB is unlikely and further diagnostic procedures should be performed without waiting for culture results.

Tuberculosis in a cohort of Vietnamese refugees after arrival in Denmark 1979-1982.

SETTING: Department of Infectious Diseases, Rigshospitalet, Copenhagen, Denmark. OBJECTIVE: To study the occurrence of tuberculosis (TB) in a cohort of immigrants from a high incidence country during the years following arrival in a low incidence country. DESIGN: Follow-up analysis in a cohort of 1983 Vietnamese refugees who arrived in Denmark during the period 1979-1982. The civil registration number could be identified for 1936 (98%) individuals from the original cohort. Date of possible death, emigration and the development of tuberculosis were determined by checking the refugees' civil registration number in the National Civil Register and the National Infectious Disease Registry for Tuberculosis. RESULTS: Tuberculosis notification for the 1936 individuals fell from 1.14% for the first 12 months to a mean of 0.08% per year during the following 5-year period. During the 16 years of follow up, 36 of the refugees developed tuberculosis, of whom 14 (39%) had had abnormal chest X-ray on arrival and 14 (39%) (including one with normal chest X-ray) had been identified as having active tuberculosis through screening on arrival. CONCLUSION: Decline in tuberculosis incidence for immigrants is very rapid if the tuberculosis infection rate is low following arrival. With a very limited TB screening programme (chest X-ray on arrival) and a passive diagnosis policy without preventive chemotherapy, it is possible to control tuberculosis among high prevalence immigrants in a low incidence country.

Effect of salmeterol is independent of previously inhaled salbutamol: a clinical controlled study.

The objective of this study was to examine the bronchodilating effect of an inhaled long acting beta2-agonist (salmeterol) after a high dose of an inhaled short acting beta2-agonist (salbutamol) in asthma patients. We used a randomized double-blind, placebo-controlled, crossover design, studying seven subjects with moderate asthma, treated with inhaled steroids and highly reversible to salbutamol and salmeterol. 1.5 h after salmeterol inhalation, the mean difference in FEV1 between salbutamol and placebo pretreatment days was 6.31% and ranged from 0.02 to 1.05%, 2.5-10.5 h after salmeterol inhalation. We concluded that the effect measured as the duration of bronchodilation of salmeterol is not decreased by previously inhaled salbutamol. We only found a trend toward an additive effect of combining salbutamol and salmeterol, probably because the high dose of salbutamol did not give room for further improvement in FEV1. In accordance with other clinical studies we were unable to demonstrate any clinical implications of the salmeterol partial beta2-antagonism known from animal and in vitro studies.

The effect of inhaled glucocorticosteroids in emphysema due to alpha1-antitrypsin deficiency.

Despite the success of inhaled steroids in controlling asthma, the benefit in patients with chronic obstructive pulmonary disease (COPD) remains controversial. Five subjects with moderate to severe emphysema due to alpha 1-antitrypsin deficiency (phenotype PiZ) were followed with daily home spirometry in a 2 x 8 weeks, randomized double-blind, placebo-controlled, crossover study of inhaled budesonide 0.8 mg b.i.d. In three of the five patients, there was a statistically significant increase in the mean forced expiratory volume in 1 s (FEV1), and in two of these patients, there was also a statistically significant increase in the mean forced vital capacity (FVC) during budesonide treatment. A significant diurnal variation in FEV1 and FVC was found in three and two patients, respectively, but did not change significantly during treatment. These findings emphasize the need for renewed evaluation of inhaled steroids in the treatment of patients with emphysema, and indicate that individual patients may have significant clinical improvement.

Diagnostic strategy for pulmonary tuberculosis in a low-incidence country: results of chest X-ray and sputum cultured for Mycobacterium tuberculosis.

The referral centre of tuberculosis in the municipality of Copenhagen, Denmark was the setting for this study, which aimed to assess the diagnostic strategy (chest X-ray and clinical mycobacteriology) in pulmonary tuberculosis. Patient records and chest X-rays were examined for all patients who had sputum or gastric lavage examined for Mycobacterium tuberculosis (Mtb) from 1 January 1992 to 30 April 1994. All chest X-rays were re-evaluated by a trained lung specialist, who did not know the results of sputum culture. Evaluation was referred to one of seven X-ray categories, and compared to the results of culture. Culture of sputum or gastric lavage were positive for Mtb in 54 (14%) of 392 patients; in 61% of 59 patients with X-ray changes thought to be due to tuberculosis (TB); in 20% of 51 patients with X-ray changes compatible with TB; in 14% of 35 patients with previous TB and radiographically active TB; in 2% of 103 patients with previous TB, but not radiographically active TB; in 1% of 112 patients with X-ray changes thought to be due to other disease; and none out of 32 patients with normal X-ray. Even in this highly selected material, it is relatively expensive to find the very few cases of active TB in patients with chest X-ray changes not suspected to be due to TB. It is recommended that: (1) examination of sputum for Mtb should always be preceded by X-ray of the chest in a low-prevalence country; (2) routine culture of sputum for Mtb is restricted to patients with X-ray changes typical or compatible with active TB; and (3) exceptions to this general rule should be made on the basis of the individual's clinical history.

Liver injury during antituberculosis treatment: an 11-year study.

SETTING: Bispebjerg Hospital, Department of Pulmonary Medicine, tuberculosis referral center for the Municipality of Copenhagen. OBJECTIVE: To evaluate routine procedure for the management of liver injury during antituberculosis treatment. DESIGN: From 1983-1993, 765 patients for whom we could trace 752 files (98%) were treated at our ward with standard Danish treatment for tuberculosis. From 1983-1986 they received a three-drug (9-month) regimen and from 1986-1993 a four-drug (6-month) regimen consisting of isoniazid, rifampicin, ethambutol + pyrazinamide. Data from a retrospective chart review. RESULTS: An increase in aspartate aminotransferase (AST) of more than twice the upper limit of normal (ULN) was recorded in 127 patients (16%). 66 had elevated AST before treatment; most of these were men with a daily alcohol consumption in excess of 60 g. In the remaining 61 patients (8%) AST increased during antituberculosis treatment. 30 of these patients were excessive alcohol consumers, and seven had alcoholic liver cirrhosis. Despite an increase in AST of median 6 x ULN (range 2-25 x ULN), it was possible to continue treatment in 31 (15 excessive alcohol consumers) or reintroduce it fully in 14 (12 excessive alcohol consumers). Only 16 patients (2%), including 11 women with no daily alcohol consumption, needed a modified regimen. These patients were older (P < 0.05), seven were jaundiced, and one had alcoholic liver cirrhosis. Hepatotoxicity was confirmed by challenge with pyrazinamide (n = 7), isoniazid (n = 6) and combined isoniazid/rifampicin (n = 1). No deaths were caused by hepatotoxicity. CONCLUSION: In spite of an increase in AST levels to approximately 6 x ULN during antituberculosis treatment, the drugs can be continued or reintroduced in full in most cases. Risk factors of hepatotoxicity included old age, female sex and extensive tuberculosis, and not alcohol consumption. Overall, hepatotoxicity during antituberculosis treatment can be monitored and managed easily.

Clinical evaluation of MPT-64 and MPT-59, two proteins secreted from Mycobacterium tuberculosis, for skin test reagents.

SETTING: Department of Pulmonary Medicine P, Bispebjerg Hospital, Copenhagen, Denmark. OBJECTIVE: To study the ability of two proteins secreted from Mycobacterium tuberculosis, MPT-64 and MPT-59 to induce delayed type hypersensitivity (DTH) reactions following intradermal administration. DESIGN: In a small scale clinical investigation, skin reactions to these antigens were compared to reactions to tuberculin PPD RT23 in 1) patients with active tuberculosis, 2) BCG vaccinated healthy subjects with close contact with tuberculous patients, and 3) BCG vaccinated healthy subjects without contact with tuberculous patients. Tests for in vitro reactivity to these antigens were carried out in similar groups. RESULTS: All subjects gave positive reaction to tuberculin PPD RT23, whereas approximately half of the subjects in each of the three groups reacted to MPT-59. Two subjects (one patient with tuberculosis and one healthy bacille Calmette-Guérin vaccinated subject without patient contact) reacted to MPT-64. The studies of cell proliferation and induction of interferon-gamma (IFN-gamma) following stimulation with tuberculin PPD and MPT-64 supported this profile of reactivity. CONCLUSION: None of the experimental skin test antigens had properties superior to tuberculin PPD RT23 in humans. The failure of MPT-64 to induce delayed type hypersensitivity reactions in the majority of tuberculosis patients is discussed, in view of the potent reactivity to MPT-64 in tuberculous guinea pigs.