Personalized medicine and chronic obstructive pulmonary disease.

PURPOSE OF REVIEW: The current review summarizes ongoing developments in personalized medicine and precision medicine in chronic obstructive pulmonary disease (COPD). Our current approach is far away of personalized management algorithms as current recommendations for COPD are largely based on a reductionist disease description, operationally defined by results of spirometry. RECENT FINDINGS: Besides precision medicine developments, a personalized medicine approach in COPD is described based on a holistic approach of the patient and considering illness as the consequence of dynamic interactions within and between multiple interacting and self-adjusting systems. Pulmonary rehabilitation is described as a model of personalized medicine. Largely based on current understanding of inflammatory processes in COPD, targeted interventions in COPD are reviewed. Augmentation therapy for α-1-antitrypsine deficiency is described as model of precision medicine in COPD based in profound understanding of the related genetic endotype. SUMMARY: Future developments of precision medicine in COPD require identification of relevant endotypes combined with proper identification of phenotypes involved in the complex and heterogeneous manifestations of COPD.

Process of pulmonary rehabilitation and program organization.

Pulmonary rehabilitation programs are highly directed to return patients suffering from chronic lung diseases to a state of self-help. These programs are largely organized as temporary interventions in a highly fragmented delivery care system for patients with chronic respiratory conditions. In an optimal health care organizational structure, pulmonary rehabilitation needs to be considered as an essential part of an individualized, integrated care process, organized from the vantage point of the patient and the patients'health continuum. Pulmonary rehabilitation programs need to become organized as patient-centered care, respectful of and responsive to individual patient preferences, needs and values. Partnering and communication skills are considered as drivers for successful rehabilitation. Assessment is considered as the cornerstone to evaluate the individual needs and problems in order to develop an individualized intervention. Pulmonary rehabilitation programs need to move away from a supply-driven functional organizational structure towards integrated structures, including the full range of medical expertise, technical skills and specialized facilities needed to compete on added value in the management of patients with chronic respiratory diseases.

Associations of depressive symptoms with gender, body mass index and dyspnea in primary care COPD patients.

BACKGROUND: It has been suggested that severe COPD is associated with depressive symptoms, possibly linked to exacerbations, dyspnea and hospitalisation. However, scarce data are available in primary care where most patients suffer from mild or moderate disease. OBJECTIVE: We aimed to reveal associations of depressive symptoms with demographic and clinical characteristics in mild to moderate COPD. METHODS: Cross-sectional data on lung function measurements, exacerbation frequency, dyspnea, comorbidity, smoking behaviour, body mass index (BMI), age, gender and depressive symptoms (Beck Depression Inventory) of 147 primary care patients were assessed in multiple logistic regression analyses. RESULTS: Patients suffered from mild to moderate obstruction (FEV1 63.6% pred, range 45.1% to 82.1%). Female gender (OR 4.8, 95% CI 2.1 to 10.8), BMI > 25 (OR 0.4, 95% CI 0.2 to 0.8) and current smoking (OR 2.3, 95% CI 1.01 to 5.3) were univariately associated with depressive symptoms, while in a multivariate logistic model only female gender (OR 4.0, 95% CI 1.6 to 9.9), BMI > 25 (OR 0.3, 95% CI 0.1 to 0.7) and dyspnea (OR 1.8, 95% CI 1.1 to 2.9) were independently associated with depressive symptoms. Conclusion. These data suggest that in primary care depressive symptoms in COPD seem to be related with female gender, BMI and dyspnea. In this study, lung function, exacerbation rate, smoking behaviour, age and comorbidity are not independently associated with depressive symptoms in COPD of mild to moderate severity.

Nutritional support in patients with chronic obstructive pulmonary disease during hospitalization for an acute exacerbation; a randomized controlled feasibility trial.

BACKGROUND & AIMS: Previous studies reported a severely impaired energy balance in COPD patients during the first days of an acute exacerbation, mainly due to a decreased energy and protein intake. The aim of the study was to investigate the feasibility and effectiveness of energy- and protein-rich nutritional supplements during hospitalization for an acute exacerbation in nutritionally depleted COPD patients. METHODS: In a randomized double-blind, placebo-controlled two-center trial, 56 COPD patients were randomized and 47 patients completed the study. Nutritional intervention consisted of 3 x 125 ml (2.38 MJ/day) and the placebo group received similar amounts of a non-caloric fluid. Medical therapy and dietetic consultation were standardized and dietary intake was measured daily. Body composition, respiratory and skeletal muscle strength, lung function and symptoms were measured on admission and on days 4 and 8 of hospitalization. RESULTS: Forty-seven percent of the patients had experienced recent involuntary weight loss prior to admission. The degree of weight loss was inversely related to resting arterial oxygen tension (r = 0.31; P < 0.05). Nutritional intervention resulted in a significant increase in energy (16% vs. placebo) and protein intake (38% vs. placebo). Mean duration of hospitalization was 9 +/- 2 days. Relative to usual care, no additional improvements in lung function or muscle strength were seen after nutritional intervention. CONCLUSIONS: Oral nutritional supplementation during hospitalization for an acute exacerbation is feasible in nutritionally depleted COPD patients and does not interfere with normal dietary intake.

Changes in pulmonary hyperinflation and bronchial hyperresponsiveness following treatment with lansoprazole in children with cystic fibrosis.

SUMMARY. In this prospective open study of 14 children with cystic fibrosis (CF), we evaluated the effect of 1 year adjuvant therapy with lansoprazole, a proton pump inhibitor (PPI), on growth, fecal fat loss, body composition and lung function. Only stable patients with pancreatic insufficiency were included, and their data were compared to those of a large Dutch pediatric normal reference population. During the use of the PPI, mean weight and height did not change significantly, while body mass index improved (P < 0.05). An immediate significant and persistent reduction of fecal acid steatocrit (P < 0.05) was demonstrated. Compared to normal Dutch children, the CF patients showed significantly decreased standard deviation scores (SDS) for total body fat (TBF, -0.966) and fat-free mass (FFM, -1.826). Under lansoprazole, TBF improved significantly (P < 0.05), while mean FFM remained unchanged. A significant improvement in total lung capacity (P < 0.05), residual volume (P = 0.055), and maximal inspiratory mouth pressure (P = 0.002) was also demonstrated. Hyperinflation tended to decrease during the use of a PPI. Daily recordings of peak expiratory flow (PEF) showed a maximal diurnal variability of 28% of recent best PEF and minimal morning PEF of 72% of recent best PEF, confirming that bronchial hyperresponsiveness is increased in CF. We conclude that adjuvant therapy with lansoprazole in young CF patients with persistent fat malabsorption, decreased fat losses and improved total body fat. Lung hyperinflation decreased, which may partly explain the improvement in inspiratory muscle performance. The simultaneous improvements in body composition and lung hyperinflation suggest a relationship between these two parameters. Further research is necessary to confirm such a relationship and to elucidate the mechanisms involved.

Acute effects of different nutritional supplements on symptoms and functional capacity in patients with chronic obstructive pulmonary disease.

BACKGROUND: Use of nutritional supplements in depleted patients with chronic obstructive pulmonary disease (COPD) requires optimization between positive effects on outcome and potential acute adverse effects on metabolism and exercise performance. OBJECTIVE: The aim of this study was to investigate the acute effects of nutritional supplements on metabolism and exercise capacity in stable COPD patients. DESIGN: In part 1, the effects of 3 different energy loads (placebo, 1046 kJ, and 2092 kJ) with a normal distribution of macronutrients were investigated in 14 COPD patients. In part 2, the effects of a fat-rich compared with a carbohydrate-rich supplement (both 1046 kJ) were studied in 11 COPD patients. The study was performed in a randomized, double-blind, crossover fashion. Metabolic and ventilatory variables were measured postprandially and during a submaximal cycle endurance exercise test. RESULTS: Overall, no immediate negative effects of the supplements were found in part 1. A slight but significant postprandial increase in respiratory quotient was found after the 1046-kJ and 2092-kJ supplements compared with placebo. There was no significant difference in metabolism or exercise capacity after a fat-rich or carbohydrate-rich supplement. Surprisingly, the change in shortness of breath (postprandial compared with preprandial) was significantly greater after the fat-rich supplement. CONCLUSIONS: An energy load up to 2092 kJ had no adverse immediate effect in COPD patients compared with placebo. The subjects who consumed the fat-rich supplement experienced more shortness of breath than did the subjects who consumed the carbohydrate-rich supplement.

Characterization of nonresponse to high caloric oral nutritional therapy in depleted patients with chronic obstructive pulmonary disease.

Nutritional support can increase body weight and physiologic function in COPD, but there are some patients who do not respond to nutritional therapy. The aim of this prospective study was to describe the nonresponse to 8 wk of oral nutritional supplementation therapy (500 to 750 kcal/d extra), implemented in an inpatient pulmonary rehabilitation program, with respect to lung function, body composition, energy balance, and systemic inflammatory profile in 24 (16 male) depleted patients with COPD. On the basis of the weight change after 8 wk, patients were divided into three groups (Group 1: weight gain < 2% of baseline body weight, n = 5; Group 2: weight gain 2 to 5%, n = 9; Group 3: weight gain >/= 5%, n = 10). Although no differences were seen in lung function and body composition, Group 1 was characterized by older age, a lower baseline dietary intake/resting energy expenditure (REE) ratio, and a greater number of users of continuous supplemental oxygen when compared with Group 3. In addition, Group 1 exhibited higher baseline concentrations of fasting glucose and LPS-binding protein than did Groups 2 and 3. The concentrations of the soluble TNF- receptors 55 and 75 were elevated in Groups 1 and 2 when compared with Group 3. Furthermore, a significant, inverse correlation coefficient between baseline dietary intake and soluble intercellular adhesion molecule was revealed (r = -0.50, p = 0.016). On linear regression analysis, age, baseline intake/REE ratio, sTNF-receptor 55, and extracellular/intracellular water (ECW/ICW) ratio were selected as independent, significant parameters contributing to a total explained variation of 78% in weight change after nutritional therapy. In conclusion, nonresponse to nutritional therapy in COPD is associated with ageing, relative anorexia, and an elevated systemic inflammatory response. Further research is needed to investigate whether these factors contribute to eventual disturbances in intermediary metabolism as reflected by the increased glucose concentration and ECW/ICW ratio.

Nutritional abnormalities and supplementation in chronic obstructive pulmonary disease.

Weight loss and muscle wasting commonly occur in patients with chronic obstructive pulmonary disease (COPD). A decreased dietary intake and elevated energy requirements underlie weight loss in these patients. Disturbances in intermediary metabolism caused by altered anabolic and catabolic mediators such as hormones, cytokines, and growth factors, and resulting in disproportionate muscle wasting have been described. Nutritional supplementation in combination with an anabolic stimulus (e.g. exercise) has been shown effective in improving functional capacity, health status, and mortality in most depleted patients. Nutritional or pharmacologic modulation of the catabolic response may further enhance the response in the near future.

Enzyme activity of rat tibialis anterior muscle differs between treatment with triamcinolone and prednisolone and nutritional deprivation.

The maximal activity of a selection of enzymes involved in muscle carbohydrate handling, citric acid cycle and fatty acyl beta-oxidation were studied after treatment with the fluorinated corticosteroid triamcinolone and compared to a similar treatment of the non-fluorinated corticosteroid prednisolone in an equipotent anti-inflammatory dose. Furthermore, because triamcinolone causes loss of body mass and muscle wasting, the effects of triamcinolone were investigated relative to a control group, with the same loss of body mass, due to nutritional deprivation. The study was performed in male Wistar rats in the following treatment groups: TR, triamcinolone treatment (0.25 mg x kg(-1) x day(-1) for 2 weeks), which resulted in a reduction of body mass (24%); ND, nutritional deprivation (30% of normal daily food intake for 2 weeks) resulting in a similar (24%) decrease of body mass as TR; PR, prednisolone treatment (0.31 mg x kg(-1) x day(-1) for 2 weeks), with a 10% increase in body mass; FF, free-fed control group, with a 12% increase in body mass in 2 weeks. Compared to FF, TR induced an increase in phosphofructokinase (PFK) activity (P < 0.01), glycogen synthase [GS(i + d)] activity (P < 0.05) and glycogen content (P < 0.01) in the tibialis anterior muscle. The PR and ND caused no alterations in PFK or citrate synthase (CS) activity compared to FF. Compared to PR, TR induced an increase in PFK (P < 0.01), CS (P < 0.05) and GS(i + d) activity (P < 0.01). Both TR and PR caused an increased muscle glycogen content, being more pronounced in TR (P < 0.05). Compared to ND, TR induced an increased CS (P < 0.05) and GS(i + d) activity (P < 0.01) and glycogen content (P < 0.01). The ND resulted in a decreased glycogen content compared to FF (P < 0.05). None of the treatments affected the activity of glycogen phosphorylase, beta-hydroxyacyl coenzyme A dehydrogenase and lactate dehydrogenase. It was concluded that corticosteroids led to an increased muscle glycogen content; however, the changes in the enzymes of carbohydrate metabolism were corticosteroid type specific and did not relate to undernutrition, which accompanied the triamcinolone treatment.

Contractile properties and histochemical characteristics of the rat diaphragm after prolonged triamcinolone treatment and nutritional deprivation.

The influence of decreased muscle mass and reduced food intake on diaphragm structure and contractility in male Wistar rats was determined after triamcinolone acetate treatment (TR: 0.5 mg per kg per day for 4 weeks) and two degrees of undernutrition (PW: pair-weight, which resulted in a similar (41%) reduction of body weight as TR; PF: pair-fed, which resulted in a moderate (13%) reduction of body weight) and a free-fed control group (FF, with an increase (9%) in body weight). energy intake of TR decreased, but based on daily measurements of food intake and body weight, energy expenditure of the TR rats was increased compared with the other groups. Body (BW) and muscle weights were reduced in proportion to the extent of undernutrition in the nutritionally deprived rates (i.e. BW and diaphragm weight of PF animals were reduced 215 and 16% respectively compared with FF, v. a. 48% and 41% reduction in the PW group). Triamcinolone-induced atrophy was limited to type II fibres (30% of type IIa and 45% of type IIx/b, p < 0.05), while severe chronic undernutrition (PW) induced a generalized fibre type atrophy in the diaphragm (23% type I, 38% type IIa and 49% type IIx/b, p < 0.05), and moderate undernutrition (PF) caused only significant type IIa atrophy (20%, p < 0.05). A leftward shift of the diaphragmatic tension-frequency relationship and a decreased fatiguability of the TR and PW bundles were observed (p < 0.01), while the PF bundles were not significantly different compared with FF. These results suggest that triamcinolone and severe undernutrition cause similar alterations in in vitro contractility of the diaphragm. The effects of triamcinolone treatment on diaphragm structure may be partly explained by the reduced food intake, but the atrophy pattern induced by severe undernutrition (PW) was different.

Physiologic effects of nutritional support and anabolic steroids in patients with chronic obstructive pulmonary disease. A placebo-controlled randomized trial.

Nutritional depletion commonly occurs in patients with COPD, causing muscle wasting and impaired physiologic function. Two hundred seventeen patients with COPD participated in a placebo-controlled, randomized trial investigating the physiologic effects of nutritional intervention alone (N) for 8 wk or combined with the anabolic steroid nandrolone decanoate (N + A). Nandrolone decanoate or placebo (P) was injected intramuscularly (women, 25 mg; men, 50 mg) in a double-blind fashion on Days 1, 15, 29, and 43. Nutritional intervention consisted of a daily high caloric supplement (420 kcal; 200 ml). Also, all patients participated in an exercise program. In the depleted patients, both treatment regimens induced a similar significant body weight gain (2.6 kg) but different body compositional changes. Particularly in the last 4 wk of treatment, weight gain in the N group was predominantly due to an expansion of fat mass (p < 0.03 versus P and N + A), whereas the relative changes in fat-free mass (FFM) and other measures of muscle mass were more favorable in the N + A group (p < 0.03 versus P). Maximal inspiratory mouth pressure improved within both treatment groups in the first 4 wk of treatment, but after 8 wk only N + A was significantly different from P (p < 0.03). Nutritional supplementation in combination with a short course of anabolic steroids may enhance the gain in FFM and respiratory muscle function in depleted patients with COPD without causing adverse side effects.