Alpha-1-antitrypsin deficiency: smoking, decline in lung function and implications for therapeutic trials.

BACKGROUND: Alpha-1-antitrypsin (AT) deficiency is a hereditary disorder associated with pulmonary emphysema. AT replacement therapy has been available for many years with only one randomised controlled trial, showing no improvement in the rate of decline in lung function. We aimed to obtain further data on the natural history of the disorder and thus to refine the criteria for future clinical trials. METHODS: Homozygotes for Pi type Z were identified among chest clinic patients and close relatives. Clinical and lung function data were obtained by means of a standardised questionnaire administered yearly for a maximum of 15 years. RESULTS: Baseline study: forced expiratory volume in 1 s (FEV1) and vital capacity (VC) were studied in 194 Pi type Z patients at registration. Past or present smoking history had the strongest relationship to reduction in FEV1 (P < 0.001), but among those who had smoked, estimated total lifetime tobacco consumption (kg) was not significantly related to FEV1. No effecton FEV1 was produced by gender, age of starting to smoke, asthma, occupation or intra-family factors in sib pairs concordant for smoking. Follow-up study: In 71 patients, the average number of annual lung function assessments per subject was 8.0 (range 6-13) and average follow-up time 97 years (range 4.2-14.9). FEV1 slope tended to be steeper in current smokers than in ex-smokers (0.05 < P < 0.1) and greatest in patients with initial FEV1 in the range 30-65% predicted. Effects on VC were less severe. Much deterioration takes place before emphysematous patients come to clinical attention. FEV1 slopes calculated using only the first four assessments have a significantly greater variance than when calculated on all assessments (F = 3.79; P < 0.01). FEV1 and VC slopes using post-bronchodilator values are greater than when using pre-bronchodilator values. CONCLUSIONS: Future trials of AT replacement therapy need rigorous standardisation of lung function testing (including bronchodilator protocol) together with an adequate period of assessment. Only randomised controlled trials should be considered valid. Therapy should ideally be started earlier than normally envisaged and before the onset of clinical emphysema.

Management of multiple drug-resistant tuberculosis.

There has been a worldwide increase in multiple drug-resistant tuberculosis (MDR-TB) which has in the past been associated with a poor prognosis. In the U.K., about half of the cases live in the London area and we have set out to obtain further information on their treatment and outcome. We examined the risk factors, drug resistance, drug treatment, sputum conversion, and outcome in patients with MDR-TB at three hospitals in South London and diagnosed during the period June 1995-January 1999. Human Immunodeficiency Virus (HIV)-positive patients were excluded. There were 760 patients resident in Lambeth, Southwark and Lewisham Health Authority (LSLHA) who were notified as tuberculosis (TB) during the time period and who were of negative or unknown HIV status. (The population of LSLHA is approx.750,000.) There was a total of 13 patients with MDR-TB, known or presumed to be HlV negative. Their median age was 28 years (range 15-53); nine (69%) were born outside the U.K. and 11 had pulmonary disease; they had organisms resistant to a median of two first-line drugs (range 2-4) and to a median of four of all drugs tested (range 2-10). They received treatment with a median of six drugs (range 3-9). Eight were followed up for at least 3 years (range 3-6) after the completion of treatment; at their last assessment none had features of active TB and all were sputum negative (smear and culture). Two returned to their countries of origin during treatment; they were sputum negative at that time. Two patients are well and continue on treatment in the U.K. One patient (known HIV negative) died following treatment failure. In conclusion, we obtained disease-free survival in eight cases of MDR-TB, known or presumed to be HIV negative and followed up for 3 years or more. The prognosis for patients treated at specialised centres is good (and better than is generally believed). We describe a new protocol for the detection and management of MDR-TB.

Multidrug-resistant tuberculosis in the United Kingdom and Lithuania.

Rates of resistance to first- and second-line drugs in multidrug-resistant tuberculosis (MDR-TB) cases in the United Kingdom were studied during 2010-2012. The highest rates for ethambutol, pyrazinamide and aminoglycosides occurred among patients originating in Eastern Europe, of whom 47% were Lithuanian. Rates of resistance to kanamycin were significantly lower (P < 0.0001) in the Lithuanian National TB Register than among Lithuanian patients resident in the United Kingdom (5% vs. 78%). In 2010, the majority of UK patients of Eastern European origin were located within the London region, whereas in 2011 the majority were located outside this region, a significant change (P = 0.01).