Bronchodilator response to nebulized salbutamol in elderly patients with stable chronic airflow limitation

The bronchodilator response to 5 mg nebulized salbutamol was studied in 20 elderly patients with stable chronic airflow limitation. Salbutamol produced significantly greater increases in FEV1 and FVC compared with placebo although there was no difference in subjective sensation of breathlessness. Spirometry can be successfully used to assess respiratory function in appropriately selected elderly patients with chronic airflow limitation.     

Prediction of exercise capacity after lung resection in patients with chronic airflow limitation

To assess the usefulness of a method for predicting postoperative peak oxygen uptake based on lost lung function after lung resection (VO2peak-PPO) and to establish the underlying physiological foundation for the relation between VO2peak-PPO and the measured postoperative value VO2peak-PO), we studied 29 patients (26 men) [age 60 (SD9)] with chronic airflow limitation [FEV1 = 66 (SD13)%] undergoing lobectomy or major pulmonary resection to treat lung cancer. The patients were assigned to groups according to whether postoperative exercise tolerance was considered to be limited by exhaustion of ventilatory reserve (LV) or not (NLV). Data to estimate postoperative pulmonary function was obtained one week before surgery: patients performed pulmonary function tests and exercise tests on a treadmill; dyspnea was also evaluated and perfusion scintigraphs were obtained. Pulmonary function, exercise tolerance and dyspnea were evaluated again approximately five months after surgery. The mean difference between VO2peak-PPO and VO2peak-PO was -0.034 (CI 0.293 to -0.348) l.min-1 and the between-group correlation coefficient was 0.76. The correlation between VO2peak-PPO and VO2peak-PO was 0.86 (SE 0.1) [0.89 (SE 0.13) for LV (n = 14) patients and 0.85 (SE 0.16) for NLV (n = 15) patients]. The correlations after adjusting for preoperative VO2peak-PPO were 0.73 (SE 0.2) and 0.35 (SE 0.27) for LV and NLV patients, respectively. We conclude that VO2peak-PPO provides a valid but only moderately precise estimate of VO2peak-PO. Only in LV patients is there a true relation between a decrease in VO2peak and loss of lung function.     

Lung transplantation in chronic obstructive lung diseases

Lung transplantation (uni- or bilateral) is an accepted treatment option for patients with end-stage chronic obstructive pulmonary disease. Pulmonary function improves significantly and 5-year-actuarial survival is more than 70% at acceptable early mortality rates. Careful evaluation of risks and benefits in necessary because of the known donor-organ shortage and the risks of life-long immunosuppressive treatment. The bronchiolitis obliterans syndrome is still a nonsolved problem in the long-term course after LTx and it can influence late graft function and patient survival.     

Reversible airflow limitation in adults with respiratory infection

The aim of the study was to determine the occurrence of airflow limitation and the frequency of significant reversibility in respiratory infections in adults without known asthma or chronic obstructive pulmonary disease (COPD). We also wanted to study the association between airflow limitation and aetiological agents diagnosed by serological analyses. Spirometry was performed in 574 adult general practice patients with upper or lower respiratory tract infection, and follow-up measurement was obtained in 429 of them. In the latter group, we also obtained paired sera for analysis of anti-bodies against respiratory viruses, chlamydial and mycoplasmal agents. Median forced expiratory volume in one second (FEV1) in all patients included was 90% of predicted; significantly lower in patients with an established diagnosis of asthma or COPD, compared to those without, 77 and 91% predicted, respectively. Among the patients without known asthma or COPD there was a strong association between low FEV1 and the symptoms cough and dyspnoea. Both acute-phase and follow-up FEV1 was measured in 395 of the patients without known asthma or COPD, and a significant increase in median value from 92 to 96% was registered. A reversibility of FEV1 of > 15% was measured in 23% of the 395 patients, uninfluenced by anti-asthma treatment in the great majority. Patients with an established viral, mycoplasmal or chlamydial infection had a significantly lower FEV1 at entry and a greater reversibility, compared to those without such aetiological diagnosis. We conclude that reversible obstruction was particularly common in the patients diagnosed as having acute bronchitis, but that it was found in the patients patients diagnosed as having upper respiratory tract infection.(ABSTRACT TRUNCATED AT 250 WORDS)     

Identification of smokers susceptible to development of chronic airflow limitation: a 13-year follow-up

2-deoxy-D-Ribose (dRib), the most reducing sugar, induces apoptosis in normal human fibroblasts, as judged by cytoplasmic shrinkage, chromatin condensation, DNA fragmentation and mitochondrial depolarization. This effect is independent from culture conditions, such as cell density and the presence or absence of serum in the culture milieu, suggesting that dRib-induced apoptosis is cell cycle-independent. dRib was found also to provoke disruption of the actin filament network and detachment from the substratum, while at the same time, interestingly, it increases the expression of several integrins and cell adhesion molecules. Furthermore, dRib was found to reduce the intracellular levels of reduced glutathione (GSH). The apoptotic process was not affected by the macromolecular-synthesis inhibitors cycloheximide and actinomycin D. On the contrary, the antioxidant N-acetyl-L-cysteine (NAC) fully blocks the dRib-induced apoptosis by preventing GSH depletion, while it also inhibits actin-filament-network disruption and mitochondrial depolarization. The above indicate that dRib induces apoptosis in human fibroblasts by a mechanism involving glutathione metabolism and oxidative stress, as well as disturbance of cytoskeletal integrity and cell adhesion.     

Noninvasive determination of cardiac output in patients with severe airflow limitation

The noninvasive measurement of cardiac output (Q) by the Indirect Fick CO2-rebreathing technique requires mixed venous P CO2 (P CO2) to be determined by the rebreathing maneuver, and Pa CO2 to be estimated from end-tidal P CO2 (PET CO2). Previous work has suggested that although P CO2 can be determined, Pa CO2 cannot be accurately estimated in patients with significant airflow limitation. Nineteen patients with cystic fibrosis who had severe airflow limitation (%FEV1, 29.3 +/- 7.12 SD) were studied during steady-state exercise at 50% of their measured maximal work capacity. Estimated Pa CO2 was slightly lower than Pa CO2 measured from blood samples obtained from an indwelling arterial catheter (measured: 45.2 +/- 4.92; estimate: 42.7 +/- 5.68 mm Hg). To calculate arterial blood content, the values derived from Pa CO2, pH, hemoglobin (Hb), and O2 saturation were compared with those derived from PET CO2 and O2 saturation, where (1) pH was assumed to be 7.40 and Hb was measured, and (2) pH was assumed to be 7.40 and Hb was assumed to be 15 g/dl (measured mean pH, 7.34; Hb, 14.4 g/dl). No difference in arterial CO2 content was seen between the three methods (measured: 47.53 +/- 5.17; estimate 1: 49.57 +/- 6.58; estimate 2: 49.12 +/- 6.61 ml/100 ml). As pH and Hb can also affect mixed venous CO2 content, the effect on Q was also assessed. Both estimates fit closely with measured Q (r2=0.77 and 0.76), with intercepts not different from zero and slopes not different from 1, and coefficients of variation of 13.5 and 14.6%. When viewed with regard to the confidence intervals for Q as a function of O2 consumption, Q was altered to a minor extent. We conclude that the use of PET CO2 to estimate Pa CO2 can give reasonable values for Q determined noninvasively in patients with severe airflow limitation.     

The MOS SF-36 health survey questionnaire in severe chronic airflow limitation: comparison with the Nottingham Health Profile

This study documents the cross-sectional, health-related quality of life (HRQOL) measures obtained at baseline for patients with severe chronic airways limitation (CAL) being assessed for home oxygen therapy (HOT) at the Flinders Medical Centre, Adelaide, South Australia. Two generic quality of life instruments, the Nottingham Health Profile (NHP) and the Medical Outcomes Study (MOS) short form 36-item questionnaire (SF-36), were administered by interview to the same patients to permit comparisons to be made between the two instruments. SF-36 mean scores were also compared with scores obtained in separate studies of a South Australian elderly general population and of groups of Australian subjects with various medical and psychiatric conditions. NHP mean scores were compared with scores from an elderly group of Adelaide residents from a household survey. HRQOL measures were obtained for 60 patients, 32 males and 28 females. At assessment for HOT, patients with severe CAL were experiencing severe impairment in their quality of life in comparison to age-matched South Australian norms, with physical disability the major limitation. There were several significant correlations between the domains of the SF-36 and the NHP which were predominantly gender-specific. Only small decrements in mental health were found with the SF-36 questionnaire. The SF-36 and the NHP appear to provide discrepant information for severely disabled CAL patients for the subjective domains of emotional and mental health.     

Theophylline for irreversible chronic airflow limitation: a randomized study comparing n of 1 trials to standard practice

Antibody-directed enzyme prodrug therapy (ADEPT) is a technique to increase antitumor selectivity in cancer chemotherapy. Our approach to this technology has been to design a mutant of human carboxypeptidase A (hCPA1-T268G) which is capable of hydrolyzing in vivo stable prodrugs of MTX and targeting this enzyme to tumors on an Ep-CAM1-specific antibody, ING1. Through the use of this >99% human enzyme which is capable of catalyzing a completely nonhuman reaction, we hope to increase ADEPT selectivity while decreasing overall immunogenicity of the enzyme-antibody conjugate. In the current report, prodrugs of the thymidylate synthase inhibitors GW1031 and GW1843 and the dihydrofolate reductase inhibitor methotrexate were studied for their wild-type and mutant hCPA enzyme hydrolysis, their in vivo stability, and their use in therapy. Prodrugs with high kcat/Km ratios for mutated versus wild-type hCPA1 were examined in vitro for their stability in human pancreatic juice, and in vivo for their stability in mouse plasma and tissues. In addition, targeting and in vivo enzyme activity studies were performed with an ING1 antibody conjugate of the mutant enzyme (ING1-hCPA1-T268G). Finally, in vivo therapy studies were performed with LS174T tumors to demonstrate proof of principle. Results indicate that prodrugs can be synthesized that are selective and efficient substrates of hCPA1-T268G and not substrates of the endogenous CPA activities; this leads to excellent in vivo stability for these compounds. In vivo conjugate targeting studies showed that the antibody-enzyme conjugate was targeted to the tumor and enzyme was initially active in vivo at the site. Unfortunately therapeutic studies did not demonstrate tumor reduction. Experiments to determine reasons for the lack of antitumor activity showed that the enzyme activity decreased as a result of enzyme instability. The results offer encouragement for additional novel mutant enzyme improvements and additional in vivo studies on this unique approach to ADEPT.     

Aspects of chronic airflow obstruction

This report questions several commonly used definitions and commonly accepted concepts. It suggest that the term, "chronic airflow obstructions," should replace the terms, "chronic obstructive pulmonary disease," "chronic obstructive lung disease," or "chronic airway obstruction," because it is flow that is obstructed. It is suggested the term, "chronic mucous hypersecretion," be used, rather than "chronic bronchitis," and that the latter be avoided. Chronic bronchitis should not be equated with narrowing of the airway and emphysema with loss of elastic recoil. Chronic bronchitis, emphysema, and lesions of the small airways probably occur together more frequently than chance will allow because of a common etiologic agent, tobacco smoke. Chronic mucous hypersecretion without other airway or parenchymal lesions seldom produces airflow obstruction and does not impair prognosis significantly. Central airways are important in chronic airflow obstruction. It is time that someone found out what is happening in subjects with abnormal results on tests of the function of small airways. The definition of "destruction" as it occurs in emphysema is deceptive, and loss of recoil and emphysema may be separate conditions. The dysfunction that occurs in emphysematous lungs is due mainly to associated airway lesions and may perhaps be due in part to the site and nature of emphysematous lesions (as opposed to loss of elastic recoil).     

Lung transplantation

Although we have not yet obtained the survival results that have been observed in heart and renal transplantation, the survival rate in lung transplantation is improving. Because the lung is the only organ that is continuously exposed to the environment after transplantation, infection continues to be the major cause of early and late morbidity and mortality. Bronchiolitis obliterans, the second most common cause of late morbidity and mortality, is a progressive and currently untreatable condition resulting in lung dysfunction. The cause of this condition after transplantation is likely multifactorial and related to processes that result in allograft lung injury, such as rejection, bacterial infection, and cytomegalovirus infection. Future improvement in intermediate and long-term survival after lung transplantation will largely depend on prevention and long-term control of infection and subclinical rejection.     

Severity of airflow limitation is associated with severity of airway inflammation in smokers

To investigate the relationship between airflow limitation and airway inflammation in smokers, we examined paraffin-embedded bronchial biopsies obtained from 30 smokers: 10 with severe airflow limitation, eight with mild/moderate airflow limitation, and 12 control smokers with normal lung function. Histochemical and immunohistochemical methods were performed to assess the number of inflammatory cells in the subepithelium and the expression of CC chemokines macrophage inflammatory protein (MIP)-1alpha and -1beta in the bronchial mucosa. Compared with control smokers, smokers with severe airflow limitation had an increased number of neutrophils (p < 0.02), macrophages (p < 0.03), and NK lymphocytes (p < 0.03) in the subepithelium, and an increased number of MIP-1alpha+ epithelial cells (p < 0.02). When all smokers were considered together, the value of FEV1 was inversely correlated with the number of neutrophils (r = -0.59, p < 0.002), macrophages (r = -047, p < 0. 012), NK-lymphocytes (r = -0.51, p < 0.006) in the subepithelium, and with the number of MIP-1alpha+ epithelial cells (r = -0.61, p < 0.003). We conclude that in smokers the severity of airflow limitation is correlated with the severity of airway inflammation and that severe airflow limitation is associated with an increased number of neutrophils, macrophages, NK lymphocytes, and MIP-1alpha+ cells in the bronchial mucosa.     

Lung transplantation in children

The first lung transplantation in the Netherlands was carried out in 1990. Since, the operation has been performed in over one hundred adults and two children (up to 16 years) with chronic respiratory insufficiency. Most lung transplantations in children are performed because of cystic fibrosis. After referral, the patient is given information about the operation and the pre- and postoperative periods, and the transplantation team advises on the time of screening. Some one-third of the children referred ultimately undergo transplantation; the others refrain from the operation, are rejected or die during the waiting period. Owing to a shortage of donor lungs the waiting period for transplantation may last over one year. A possible but controversial solution is donation of a pulmonary lobe by a close relative. Undergoing lung transplantation places a heavy (psychic) burden on the patient and his parents. Every patient after lung transplantation goes through an average of two or three periods of acute rejection. Chronic rejection occurs in 20-40%. Other complications are connected to medication (infections, renal dysfunction) or to the underlying disease (diabetes mellitus in cystic fibrosis). The percentages of survival for 1, 2 and 4 years are approx. 60-70, 55-60 and 30-50, dependent in part on the type of lung transplantation (unilateral, bilateral or combined heart-lung transplantation). A reasonable condition of the patient owing to timely referral is a positive prognostic factor.     

Lung transplantation in cystic fibrosis

PURPOSE: To assess the non-cutaneous involvement in primary B-cell non-Hodgkin's lymphoma (NHL) of the skin. PATIENTS AND METHODS: Data from 45 patients with B-cell NHL of the skin were retrospectively analysed. The patients were diagnosed on histologic and immunocytochemical grounds between June 1977 and July 1993, and 14 cases were selected for their exclusively cutaneous initial involvement. Initial treatment, response to therapy, disease-free survival characteristics of relapse and therapeutic sequence were evaluated in every case. RESULTS: Cutaneous involvement presented as nodules or patches, on a single location, in 12 cases, or disseminated, in 2 others. No prognostic factor could be identified, and complete remission was attained in all cases. Cutaneous relapse was seen in 7 patients after 4 to 108 months since diagnosis. Extracutaneous dissemination was not seen in any case, and 13 patients are alive and disease-free. A 90 year-old woman died of toxic complications. CONCLUSIONS: The clinical facts reported here confirm the not too aggressive behaviour of certain B-cell cutaneous NHL, probably related with their origin on the skin itself.     

The natural history of chronic airflow obstruction

A prospective epidemiological study of the early stages of the development of chronic obstructive pulmonary disease was performed on London working men. The findings showed that forced expiratory volume in one second (FEV1) falls gradually over a lifetime, but in most non-smokers and many smokers clinically significant airflow obstruction never develops. In susceptible people, however, smoking causes irreversible obstructive changes. If a susceptible smoker stops smoking he will not recover his lung function, but the average further rates of loss of FEV1 will revert to normal. Therefore, severe or fatal obstructive lung disease could be prevented by screening smokers' lung function in early middle age if those with reduced function could be induced to stop smoking. Infective processes and chronic mucus hypersecretion do not cause chronic airflow obstruction to progress more rapidly. There are thus two largely unrelated disease processes, chronic airflow obstruction and the hypersecretory disorder (including infective processes).     

Lung transplantation for lymphangioleiomyomatosis

BACKGROUND: Lymphangioleiomyomatosis is a rare disease of unknown origin that usually leads to progressive deterioration of lung function and eventual death from respiratory failure. It occurs in women of reproductive age and people with tuberous sclerosis. Lung transplantation is a recent therapeutic approach. METHODS: We conducted a retrospective study by questionnaire of 34 patients, treated at 16 transplantation centers, who underwent lung transplantation for end-stage lymphangioleiomyomatosis between 1983 and 1995. RESULTS: Of the 34 patients, 27 received single-lung transplants; 6, bilateral transplants; and 1, a heart-lung transplant. As of August 31, 1995, the actuarial survival calculated by the Kaplan-Meier method was 69 percent after one year and 58 percent after two years. Eighteen patients were alive 33 +/- 20 months (range, 3 to 74) after transplantation. Forced expiratory volume in one second increased from 24 +/- 12 percent of the predicted value before transplantation to 48 +/- 16 percent six months after transplantation. Five early deaths (within one month) were due to hemorrhage (in one patient), acute lung injury (in three), and dehiscence of the bronchial anastomosis (in one). Eleven late deaths (after one month) were due to infections (in eight patients), bronchiolitis obliterans (in two), and metastatic nephroblastoma (in one). Disease-associated problems were extensive pleural adhesions in 18 patients, leading to moderate-to-severe intraoperative hemorrhage in 4; pneumothorax in the native lung after single-lung transplantation in 6 patients; postoperative chylothorax in 3; and recurrent lymphangioleiomyomatosis in the allograft in 1 patient, who died of disseminated aspergillosis. CONCLUSIONS: Although disease-related complications are frequent, lung transplantation can be a valuable therapy for patients with end-stage lymphangioleiomyomatosis.     

Expiratory flow limitation in COPD patients after single lung transplantation

Expiratory flow limitation and dyspnea during resting breathing are common in patients with severe chronic obstructive pulmonary disease (COPD). Although single lung transplantation (SLT) is used to treat end-stage COPD, its effects on flow limitation and dyspnea are not well established. We assessed expiratory flow-limitation and dyspnea in 13 COPD patients after SLT at rest in the sitting and supine positions by applying negative pressure at the mouth during tidal expiration (negative expiratory pressure [NEP] technique). If NEP increases flow throughout the control tidal volume (VT), flow limitation is absent (not flow limited [NEL]). If NEP does not increase flow during part of the control VT, flow limitation is present. After SLT, lung function improved in all but one patient. Twelve patients were NFL during resting breathing in both positions studied. The patient whose lung function did not improve after SLT was flow-limited (FL) both when seated and supine. This patient also exhibited moderately severe chronic dyspnea (Medical Research Council [MRC] score = 3). In the nine other patients in whom dyspnea was assessed, it was slight (MRC score = 1). In conclusion, after SLT for end-stage COPD, expiratory flow limitation at rest is uncommon in both the seated and supine positions. This is consistent with the finding that after SLT the degree of chronic dyspnea is generally slight.     

Lung transplantation for cystic fibrosis

This reprint of an article that first appeared in Nucleonics in 1966 provides a unique perspective of the introduction of the cyclotron into clinical medicine and medical research. The cyclotron offers a potentially powerful tool to biomedical centers. With this accelerator one can produce a variety of short-lived nuclides that are unavailable from other sources.     

Lung transplantation for pulmonary sarcoidosis

Patients with end-stage sarcoidosis have now undergone lung transplantation successfully with good short-term and intermediate-term results. Lung transplantation for sarcoidosis requires several considerations unique to this disease. Selection of pulmonary sarcoidosis patients for transplantation requires that medical therapy has been exhausted. This may involve the use of corticosteriods and alternative medications. Causes of pulmonary dysfunction other than pulmonary sarcoidosis, such as bronchiectasis and myocardial sarcoidosis, must be excluded before candidates are considered for transplantation. The extent and severity of extrapulmonary disease must also be assessed and may preclude lung transplantation. The presence of mycetomas is considered a relative contra-indication by some transplant centres and an absolute contra-indication by others. Relatively few patients with pulmonary sarcoidosis have undergone transplantation and, therefore, there are few data on outcome. Sarcoidosis frequently recurs in the allograft, but rarely causes symptoms or pulmonary dysfunction. More severe acute rejection episodes may occur in sarcoidosis transplant recipients, although at present there is no evidence of an increased risk of obliterative bronchiolitis or increased mortality.