Axel Kok-Jensen

Does alpha1-antitrypsin augmentation therapy slow the annual decline in FEV1 in patients with severe hereditary alpha1-antitrypsin deficiency? Wissenschaftliche Arbeitsgemeinschaft zur Therapie von Lungenerkrankungen (WATL) alpha1-AT study group

Patients with severe hereditary alpha1-antitrypsin deficiency (alpha1-ATD) face a high risk of developing emphysema at a young age. Intravenous augmentation therapy with purified human alpha1-antitrypsin (alpha1-AT) is now available. However, a controlled trial to show its efficacy has never been carried out. The aim of this study was to compare the decline in forced expiratory volume in one second (deltaFEV1) between Danish patients who had never received augmentation therapy and German patients treated with weekly infusion of alpha1-AT. From the files of the Danish alpha1-ATD register, 97 exsmokers, with a PiZ phenotype and for whom results of at least two lung function measurements with an interval of at least 1 yr were available, were identified. From a German group of patients treated with weekly infusions of alpha1-AT, 60 mg x kg(-1) body weight, 198 exsmokers, with biannual lung function measurements were identified. The deltaFEV1 was compared between the two treatment groups by random effects modelling. The deltaFEV1 in the treated group was significantly lower than in the untreated group, with annual declines of 53 mL x yr(-1) (95% confidence interval (95% CI) 48-58 mL x yr(-1)) and 75 mL x yr(-1) (95% CI 63-87 mL x yr(-1)), respectively (p=0.02). The two groups differed with respect to gender and initial FEV1% predicted. Gender did not have any influence on the deltaFEV1. Stratification by initial FEV1% pred showed a significant effect of the treatment only in the group of patients with an initial FEV1% pred of 31-65%, and deltaFEV1 was reduced by 21 mL x yr(-1). This nonrandomized study suggests that weekly infusion of human alpha1-antitrypsin in patients with moderately reduced lung function may slow the annual decline in forced expiratory volume in one second.

Prospective Evaluation of a Whole-Blood Test Using Mycobacterium tuberculosis-Specific Antigens ESAT-6 and CFP-10 for Diagnosis of Active Tuberculosis

ABSTRACT A new immunodiagnostic test based on the Mycobacterium tuberculosis-specific antigens CFP-10/ESAT-6(QFT-RD1) has been launched as an aid in the diagnosis of latent tuberculosis (TB) infection (LTBI). The aim of this study was to evaluate this test for the diagnosis of active TB. Eighty-two patients with suspicion of TB and 39 healthy BCG-vaccinated persons were enrolled. Forty-eight had active TB, 25 did not, and 9 were excluded. Sensitivity and specificity of the test for active TB were evaluated in a prospective blinded manner in patients suspected of TB. The sensitivity of the QFT-RD1 was 85% (40/48; confidence interval [CI], 75 to 96), and it was higher than the sensitivity of microscopy, 42% (20/48; CI, 27 to 56; P = 0.001), and culture, 59% (27/46; CI, 44 to 73; P = 0.009). Of patients with extrapulmonary TB, 92% (12/13) were QFT-RD1 positive, whereas only 31% (4/13) were positive by microscopy and 42% (5/12) by culture (P < 0.05), and 87% (13/15) of those who were negative by both microscopy and culture were QFT-RD1 positive. By combining microscopy and culture with the QFT-RD1 test, sensitivity increased to 96% (CI, 90 to 102). Ten of 25 (40%) non-TB patients were QFT-RD1 positive, resulting in a specificity of 60%. However, 80% (8/10) of these had risk-factors for TB, indicating latent infection in this group. In healthy controls, only 3% (1/39) were QFT-RD1 positive. In conclusion, the QFT-RD1 test is sensitive for diagnosis of TB, especially in patients with negative microscopy and culture. The accuracy of the QFT-RD1 test will vary with the prevalence of LTBI. We suggest that the QFT-RD1 test could be a very useful supplementary tool for the diagnosis of TB.

Mannose-Binding Lectin Polymorphisms in Clinical Tuberculosis

Mannose-binding lectin (MBL) mediates protection against infections by using the complement system, but certain microorganisms may increase infectivity by exploiting this host defense system. Thus, it has been speculated whether genetically determined low MBL levels may confer partial protection against certain intracellular microorganisms, such as Mycobacterium tuberculosis. We investigated MBL alleles in 109 culture-positive human immunodeficiency virus-uninfected patients with tuberculosis living in Denmark and 250 white control subjects. Patients and control subjects were divided into 3 different groups defined by undetectable, low, and high serum MBL concentrations, which correlates to deficient, low, and high expressing MBL genotypes. A significantly decreased frequency of patients with the low-expressing MBL genotype was observed in white patients compared to control subjects. The same tendency also was observed in patients of other ethnic origin. It may be hypothesized that heterozygosity for MBL variant alleles, which encodes low serum MBL levels, is associated with protection against clinical tuberculosis.

Persistent High Incidence of Tuberculosis in Immigrants in a Low-Incidence Country

Immigration from areas of high incidence is thought to have fueled the resurgence of tuberculosis (TB) in areas of low incidence. To reduce the risk of disease in low-incidence areas, the main countermeasure has been the screening of immigrants on arrival. This measure is based on the assumption of a prompt decline in the incidence of TB in immigrants during their first few years of residence in a country with low overall incidence. We have documented that this assumption is not true for 619 Somali immigrants reported in Denmark as having TB. The annual incidence of TB declined only gradually during the first 7 years of residence, from an initial 2,000 per 100,000 to 700 per 100,000. The decline was described by an exponential function with a half-time of 5.7 (95% confidence interval 4.0 to 9.7) years. This finding seriously challenges the adequacy of the customary practice of screening solely on arrival.

Risk of Mycobacterium tuberculosis Transmission in a Low-Incidence Country Due to Immigration from High-Incidence Areas

ABSTRACT Does immigration from a high-prevalence area contribute to an increased risk of tuberculosis in a low-incidence country? The tuberculosis incidence in Somalia is among the highest ever registered. Due to civil war and starvation, nearly half of all Somalis have been forced from their homes, causing significant migration to low-incidence countries. In Denmark, two-thirds of all tuberculosis patients are immigrants, half from Somalia. To determine the magnitude ofMycobacterium tuberculosis transmission between Somalis and Danes, we analyzed DNA fingerprint patterns of isolates collected in Denmark from 1992 to 1999, comprising >97% of all culture-positive patients (n = 3,320). Of these, 763 were Somalian immigrants, 55.2% of whom shared identical DNA fingerprint patterns; 74.9% of these were most likely infected before their arrival in Denmark, 23.3% were most likely infected in Denmark by other Somalis, and 1.8% were most likely infected by Danes. In the same period, only 0.9% of all Danish tuberculosis patients were most likely infected by Somalis. The Somalian immigrants in Denmark could be distributed into 35 different clusters with possible active transmission, of which 18 were retrieved among Somalis in the Netherlands. This indicated the existence of some internationally predominant Somalian strains causing clustering less likely to represent recent transmission. In conclusion, M. tuberculosis transmission among Somalis in Denmark is limited, and transmission between Somalis and Danes is nearly nonexistent. The higher transmission rates between nationalities found in the Netherlands do not apply to the situation in Denmark and not necessarily elsewhere, since many different factors may influence the magnitude of active transmission.

Survival of patients with severe alpha 1-antitrypsin deficiency with special reference to non-index cases.

BACKGROUND--Previous estimates of the survival times of patients with alpha 1-antitrypsin deficiency have been based on selected patients. METHODS--The survival times of 397 patients with severe alpha 1-antitrypsin deficiency identified by pulmonary impairment (index cases) or through family studies (non-index cases) were compared. RESULTS--The overall median survival time was 54.5 years with no significant difference between men and women. Survival for index cases was less than for the non-index cases regardless of smoking history (49.4 years and 69.3 years respectively). When index and non-index cases were analysed separately there was no difference between the survival of smokers and never smokers in the index group. In the non-index group smokers had a shorter survival time than never smokers. The survival time of never smokers was similar to that of the normal Danish population. CONCLUSIONS--The prognosis of severe alpha 1-antitrypsin deficiency is better than previously assumed and, although smoking is a major risk factor, the development of emphysema in patients with severe alpha 1-antitrypsin deficiency is multifactorial.

Clinical features and prognosis of life time non-smokers with severe alpha 1-antitrypsin deficiency.

BACKGROUND The hereditary disorder α1-antitrypsin deficiency is characterised by development of severe emphysema at an early age with smoking being the most significant additional risk factor. The purpose of the present paper was to analyse potential risk factors other than smoking for emphysema and to estimate the prognosis of life time non-smokers. METHODS Patients were identified through the files of the Danish α1-antitrypsin deficiency register which contains information on more than 700 persons with the condition. Many of the patients, the non-index cases, were identified from family studies. RESULTS There were 75 life time non-smokers with PiZ (27 index cases and 48 non-index cases) aged 20 years or more at entry. Twenty one subjects died during the follow up period. The Standardised Mortality Ratio (SMR) was 3.0 (95% confidence intervals (CI) 1.9 to 4.6). There was no significant difference in SMR between males and females. The SMR was 8.8 (95% CI 5.0 to 14) for the index cases and 0.96 (95% CI 0.3 to 2.3) for the non-index cases based on five deaths. The overall mean % predicted forced expiratory volume in one second (FEV1) at entry was 83% with a significant difference between index cases (54%) and non-index cases (100%) (p<0.001). The difference in the ratio of FEV1 to forced vital capacity (FVC) was also highly significant with values of 0.57 and 0.79 for index and non-index cases, respectively (p<0.001). In the non-index group only three had an FEV1% predicted of less than 70%. CONCLUSIONS Occupational exposure to airway irritants did not have any significant influence on the development of emphysema. Only a few life time non-smokers develop severe emphysema; most never develop pulmonary symptoms and thus remain undetected unless family members of index cases are screened.

Long-term performance of a hand held spirometer.

BACKGROUND: A study was undertaken to test the long term performance of a small hand held spirometer for self-administered serial spirometric testing. METHODS: Thirty turbine pocket spirometers (MicroMedical DiaryCard) were used in a clinical trial on 22 emphysematous patients with severe alpha 1-antitrypsin deficiency. The spirometers were able to store the date, time, forced expiratory volume in one second (FEV1), forced vital capacity (FVC), peak expiratory flow (PEF), and flow-volume loop for each blow. Every four weeks when the patients came for alpha 1-antitrypsin infusions the performance of their spirometer was checked before and after retrieval of the data from the spirometer. Calibration checks were threefold and included volume calibration with a 1.0 litre and 3.0 litre syringe, and flow calibration with a decompression calibrator. RESULTS: After two years of study the mean number of spirometric recordings performed per spirometer was 693 (range 237-1178), and the mean number of calibration checks was 33 (range 2-57). The coefficient of variation of the calibration signal was 1-2% for syringes and 0.5-1% for the decompression calibrator. The bearings of one turbine exhibited excessive friction after 17 months. None of the other 29 instruments showed drift, and a general drift of all spirometers towards larger or smaller readings could not be shown. However, unforeseen problems in the stability of the calibrating devices were observed. CONCLUSIONS: The small hand held turbine spirometers are suitable for long term patient-administered serial spirometric testing. The two year durability is acceptable and the long term reproducibility excellent.

Intermediate α1-antitrypsin deficiency PiSZ: a risk factor for pulmonary emphysema?

It is well documented that the severe hereditary disorder alpha 1-antitrypsin deficiency (alpha 1ATD) PiZZ is a strong risk factor for emphysema, especially among smokers, but the role of intermediate alpha 1ATD PiMZ and PiSZ in the development of emphysema remains uncertain. In this study, we have evaluated mortality and lung function of 94 persons with intermediate alpha 1ATD PiSZ of whom 66 were non-index cases, i.e. persons ascertained through family studies. The index cases and the non-index cases were similar with respect to sex, age and follow-up time, but differed in smoking habits and FEV1. Among the smokers there was no significant difference in pack-years between index cases and non-index cases. The overall Standardized Mortality Ratio (SMR) was 1.6 (95% confidence intervals (CI): 0.8-2.7). For the index cases the SMR was 4.3 (95% CI: 1.9-8.5) and for the non-index cases it was 0.8 (95% CI: 0.3-1.8). In the index group six patients died of pulmonary emphysema, one of pulmonary fibrosis, and one of colon cancer. In the non-index group two died of pulmonary emphysema, two of pneumonia, and one of cerebral haemorrhage. The mean initial FEV1% predicted among the index cases was 59% compared with 94% among the non-index cases. Based on the analysis of the non-index cases it is concluded that only a small fraction of persons with the PiSZ phenotype are at increased risk of developing pulmonary emphysema, and at an older age than persons with the PiZ phenotype.

Decline in pulmonary function in patients with α1-antitrypsin deficiency

Sixty-five patients with severe alpha1-antitrypsin (AAT) deficiency (phenotype PiZ) were followed with spirometry at regular intervals of one year and a median observation period of four years.The annual decline in pulmonary function was adjusted for sex, age and height by division with the predicted normal pulmonary function. The median decline in FEV1 was 1.9% predicted/year. The rate of decline was independent of age and pulmonary function, except for patients with FEV1 below 25% of predicted normal.There was a tendency towards a slower median decline in FEV1 in exsmokers (1.7% predicted/year) compared to smokers (3.8% predicted/year) and never-smokers (3.7% predicted/year), however, this difference was not significant (p > 0.1). At the time of diagnosis smokers and ex-smokers had a lower FEV1 (44 and 38% predicted) than never-smokers (85% predicted) (p < 0.02), and smokers and ex-smokers were generally younger (median age 44 and 42 years, respectively) than never smokers (median age 55 years) (p > 0.1).Our data indicate that smokers as well as nonsmokers with severe AAT deficiency are at risk of developing pulmonary emphysema. The disease seems to appear later in nonsmokers, though once initiated it progresses at the same rate.