Malnutrition in advanced lung disease

INTRODUCTION — Malnutrition in advanced lung diseases like chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) is a complex and multifactorial problem reflecting the complex interplay of systemic inflammation that leads to cachexia, decreased nutrition from poor intake, and reduced exercise tolerance from sarcopenia and dyspnea [1].

The pathophysiology and treatment of malnutrition in patients with advanced lung disease is reviewed here. The management of stable COPD, the assessment of nutritional status, and nutritional support in critical illness are discussed separately. (See "Stable COPD: Initial pharmacologic management" and "Assessment and management of anorexia and cachexia in palliative care" and "Nutrition support in intubated critically ill adult patients: Initial evaluation and prescription".)

DEFINITIONS

●Malnutrition – Consensus statements from numerous organizations define malnutrition using a variety of features: nonvolitional weight loss, low body mass index (BMI), reduced muscle mass, reduced food intake, and inflammation due to underlying chronic disease or injury [2-4]. This definition, and others, merge the effect of wasting due to inflammation with that resulting from starvation, and do not identify clearly which patients will respond to nutritional interventions [5]. Moreover, undernourishment does not fully explain the loss of muscle function seen in patients with advanced lung disease. (See "Geriatric nutrition: Nutritional issues in older adults", section on 'Diagnostic criteria for malnutrition'.)

●Cachexia – A consensus definition for cachexia incorporates weight loss >5 percent in the last 12 months in addition to three out of five criteria: (1) decreased muscle strength; (2) fatigue; (3) anorexia; (4) low fat-free mass index (FFMI); and (5) evidence of increased inflammatory markers (eg, C-reactive protein [CRP], interleukin [IL]-6), anemia, or low serum albumin [6]. Cachexia is distinct from starvation and age-related loss of muscle mass. While all patients with cachexia have malnutrition, cachexia is not always present in patients who are malnourished. Anorexia and inflammation are common features of cachexia. Pulmonary cachexia refers to the loss of fat-free body mass in patients with advanced lung disease.

●Sarcopenia – Sarcopenia is defined as low skeletal muscle mass and reduced muscle function (eg, low handgrip strength or slow gait speed) [7]. Sarcopenia can occur as a component of aging and/or in association with a range of conditions, such as chronic lung disease [1,7,8]. Low muscle mass with normal muscle strength is considered to be a consequence of malnutrition rather than sarcopenia. (See "Geriatric nutrition: Nutritional issues in older adults", section on 'Terminology'.)

FREQUENCY OF MALNUTRITION — Disease-related malnutrition has been identified in 30 to 60 percent of inpatients with chronic obstructive pulmonary disease (COPD) and correlates with disease severity [9]. The precise incidence of undernutrition reflects the methods used to define nutritional status [6]. Approximately, 20 to 50 percent of patients with COPD weigh less than 90 percent of ideal body weight and are considered underweight [10]. For example, in the Intermittent Positive-Pressure Breathing (IPPB) trial, 24 percent of the patients were underweight [11]. In the same study, among patients with a forced expiratory volume in one second (FEV₁) of less than 35 percent predicted, 50 percent had malnutrition.

The prevalence of cachexia is approximately 5 percent in COPD and increases with worsening Global Initiative for Chronic Obstructive Pulmonary Disease (GOLD) spirometric stage and Medical Research Council dyspnea score [12]. Unintentional weight loss associated with cachexia is an independent risk factor for mortality.

Patients with idiopathic pulmonary fibrosis (IPF) are similarly at risk of malnutrition. In a referral population of 81 patients with IPF, malnutrition (based on low fat-free mass index) was identified in 28 percent [13]. A separate study of 210 patients with IPF found that 19 percent had >5 percent weight loss [14].

CONTRIBUTING FACTORS — While the exact pathogenesis of pulmonary cachexia remains unclear, it seems likely that a disease-induced energy imbalance promotes cachexia and muscle wasting [15]. Factors contributing to energy imbalance include changes in metabolism and caloric intake, aging, disuse atrophy, tissue hypoxia, inflammation, and medications [11]. Given that only a minority of patients with lung diseases like chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) develop cachexia, there are likely genetic polymorphisms that underlie differential susceptibilities [1,13,16,17].

Metabolism and caloric intake — The basal metabolism in patients with advanced lung disease does not follow the expected age-related decline seen in normal individuals [18]. Many patients are hypermetabolic (consume more calories per kg on calorimetric measures), probably because of the increased work of breathing. As an example, patients with COPD can have a 10 times increase in daily energy expenditure for respiratory muscles over the baseline of 36 to 72 calories per day in a patient with normal lung function [19].

Despite hypermetabolism, COPD patients often have a reduced dietary intake [20], due in part to an alteration in appetite regulation, which may be mediated by systemic inflammation [21,22].

Aging — COPD and IPF tend to be diseases of older adults. With normal aging, body composition changes as individuals progressively lose nonfat body mass (primarily muscle tissue) and progressively increase fat stores. The decline in muscle mass reduces muscle strength and decreases the basal metabolic rate. The net result of these alterations is a reduction in exercise capacity. (See "Exercise physiology" and "Geriatric nutrition: Nutritional issues in older adults", section on 'Malnutrition'.)

Aging also causes a number of changes that can reduce exercise capacity independent of senescent cardiopulmonary and muscle function. As an example, osteoporosis is more common in older individuals (particularly those with a history of smoking and significant glucocorticoid use) and can contribute to vertebral fractures that produce kyphosis, pain, decreased diaphragmatic excursion, and impaired clearance of respiratory secretions. (See "Clinical manifestations, diagnosis, and evaluation of osteoporosis in postmenopausal women" and "Clinical features and evaluation of glucocorticoid-induced osteoporosis".)

Muscle wasting — Muscle wasting in advanced lung disease is likely due to a mixture of poor nutrition, deconditioning, aging, systemic inflammation, and medication (eg, oral glucocorticoids). Reduced cardiopulmonary reserve limits the physical activity of patients with advanced lung disease causing deconditioning. The deleterious effect of limited activity on muscle wasting is supported by a study that found that inactive older patients have greater loss of muscle mass than active age-matched controls [23]. In a separate study, quadriceps strength and endurance were reduced in patients with fibrotic lung disease compared with healthy, age-matched controls [24]. Muscle wasting, in turn, probably further decreases cardiopulmonary reserve, creating a vicious cycle. (See "Geriatric nutrition: Nutritional issues in older adults" and "Geriatric nutrition: Nutritional issues in older adults", section on 'Sarcopenia'.)

Patients with COPD also suffer from a loss of the peripheral muscle oxidative phenotype, which renders their muscles less energy efficient and more prone to oxidative stress [25]. This may augment loss of muscle mass.

Hypoxia — Adequate tissue oxygenation requires appropriate matching of oxygen demand and delivery at the cellular level. In patients with advanced lung disease, the increased work of breathing further increases oxygen demand, while the ability to respond to these increased demands is limited [26]. This phenomenon is best described in patients with emphysema, where a reduced ability to augment cardiac output results in a limitation of oxygen delivery [27,28]. Blood flow is maintained to critical sites such as the ventilatory muscles, the heart, and the central nervous system, while peripheral tissues such as skeletal muscles develop an oxygen and nutrient debt [29].

Inflammation — Any chronic inflammatory condition can theoretically contribute to weight loss, particularly in patients who are also hypermetabolic. A 2020 secondary analysis demonstrated that inflammation can negate the benefit of interventional nourishment [30]. A variety of cytokines have been associated with wasting syndromes in COPD, including tumor necrosis factor alpha (TNF-a) [31-33], soluble intercellular adhesion molecule (sICAM) [21], soluble TNF receptor [34], and interleukin-6 [35].

Chronic inflammation is associated with increased oxidative stress (an imbalance between the production of free radicals during exercise and neutralization by antioxidants), a common finding in the skeletal muscle of patients with COPD [36]. The ensuing decreased oxidative capacity of skeletal muscle renders it more susceptible to the toxic effects of free radicals and may cause muscle wasting [37]. In addition, a stress-induced shift towards a higher percentage of type II fibers increases susceptibility of the muscle to atrophy from inflammation and hypoxia. The loss of oxidative compensatory mechanisms in COPD may therefore accelerate loss of muscle mass, reducing muscle quantity in addition to muscle quality [15,38].

Medications — Glucocorticoids, which are frequently used to treat exacerbations of COPD, play an important role in wasting syndromes by inhibiting protein synthesis and promoting protein catabolism, despite their usual effect to increase appetite. The muscle wasting effects of glucocorticoids (also known as glucocorticoid-induced myopathy) appear dose-related, with doses >60 mg/day leading to reductions in respiratory muscle strength and a delay in the recovery of muscle function for several weeks [39]. The effects of low-dose glucocorticoids (<20 mg/day) are more controversial; some studies have revealed no effect on respiratory muscle strength in individuals with normal respiratory function, but reduced inspiratory and expiratory muscle strength in patients with advanced lung disease [40,41]. The extent to which low-dose glucocorticoids cause changes in body composition is unclear. (See "Major adverse effects of systemic glucocorticoids" and "Major side effects of inhaled glucocorticoids" and "Glucocorticoid-induced myopathy".)

EVALUATION AND DIAGNOSIS — In patients with advanced lung disease, we recommend evaluation and monitoring for pulmonary cachexia or concerning weight loss approximately every 6 to 12 months or at the time of routine visits. The presence of pulmonary cachexia should be suspected in patients with weight loss >5 percent, a weight <90 percent of ideal body weight (calculator 1), or a body mass index (BMI) ≤20 (calculator 2). In clinical practice, these surrogate measures are often sufficient to make a diagnosis. The approach to assessment and diagnosis of malnutrition are discussed separately (see "Nutrition support in intubated critically ill adult patients: Initial evaluation and prescription" and "Geriatric nutrition: Nutritional issues in older adults", section on 'Diagnostic criteria for malnutrition'). Laboratory tests, such as albumin and transferrin, are also generally reserved for research purposes and are not routinely used to assess nutritional status in outpatients. (See "Assessment and management of anorexia and cachexia in palliative care", section on 'Clinical assessment'.)

When evaluating patients for weight loss or muscle weakness, it is prudent to assess potentially reversible metabolic abnormalities, such as thyroid dysfunction, adrenal insufficiency, or hypogonadism (in male patients). Additional studies such as a complete blood count, C-reactive protein (CRP), and chest radiograph may also be appropriate. (See "Assessment and management of anorexia and cachexia in palliative care" and "Geriatric nutrition: Nutritional issues in older adults".)

MANAGEMENT — The association of weight loss and muscle wasting with poor exercise tolerance, morbidity, and mortality in chronic obstructive pulmonary disease (COPD), provides the rationale for interventions to improve nutritional status (see 'Effect on mortality and lung function' below). For patients with advanced lung disease and concerning weight loss or other criteria for pulmonary cachexia, we advise a combination of exercise, control of inflammation (eg, smoking cessation), and nutritional support (diet and oral supplements), reserving medication for patients who fail to improve with these interventions [42].

General measures for prevention and treatment — The optimal methods for prevention and treatment of pulmonary cachexia are not known. The following interventions are usually included in the treatment plan reflecting the observation that supplemental nutrition alone is usually insufficient to improve functional exercise capacity [43]. (See 'Efficacy of nutritional support' below.)

●Optimization of lung function – Reducing the work of breathing would theoretically reduce caloric expenditure. In addition, improved lung function should reduce dyspnea when eating, thus improving caloric intake, and enable adherence to an exercise program. (See "Stable COPD: Initial pharmacologic management" and "Stable COPD: Follow-up pharmacologic management".)

●Regular exercise – Exercise has been shown to both improve the effectiveness of nutritional therapy and stimulate appetite [20]. (See "Pulmonary rehabilitation" and "Respiratory muscle training and resting in COPD".)

●Improvement of oxygen delivery to the tissues – In addition to optimization of lung function noted above, efforts to increase oxygen delivery at the tissue level may improve muscle function. Interventions may include supplemental oxygen therapy, correction of anemia, and optimization of cardiac function. (See 'Hypoxia' above and "Long-term supplemental oxygen therapy" and "Pulmonary hypertension due to lung disease and/or hypoxemia (group 3 pulmonary hypertension): Epidemiology, pathogenesis, and diagnostic evaluation in adults".)

●Control of inflammation – When present, eosinophilic airway inflammation in COPD is generally treated with inhaled glucocorticoids. Oral glucocorticoids are used sparingly due to their many adverse effects. (See "Stable COPD: Initial pharmacologic management" and "Stable COPD: Initial pharmacologic management", section on 'Alternative approaches'.)

Nutritional interventions — The optimum method for nutritional repletion is unknown. While fat is associated with less CO₂ production than carbohydrates, the benefit of high-fat dietary supplementation in pulmonary disease over simple calorie supplementation is unproven. The clinician should be vigilant for treatable inflammatory processes and avoid treating all weight loss as an issue solely related to inadequate intake. Increasing appropriate macronutrient intake can be very difficult in the setting of advanced lung disease because of fatigue and dyspnea (interferes with food preparation and consumption), chronic sputum production (alters the taste of food), flattening of the diaphragm (causes early satiety), depression, and side effects of medications (eg, nausea, indigestion) [19]. To circumvent these problems, the following have become accepted components of nutritional therapy for patients with advanced lung disease to use as part of their normal diet [19], although formal study is lacking:

●Adequate calories to meet or slightly exceed their basal energy expenditure; consultation with a registered dietician to develop a nutritional prescription for food intake is often helpful

●Small, frequent meals with proportionately more fat and protein (eg, eggs, fish, lean meat, nuts) and less carbohydrate to increase caloric density

●Meals requiring little preparation (eg, microwaveable, liquid supplements)

●Rest before meals

Beyond these general measures' focus on optimization of the normal diet, the role of the following individual nutritional supplements has been assessed:

●Oral nutrition supplements – For patients with malnutrition related to advanced lung disease, we suggest providing nutritional supplements, which have shown modest benefit in improving body weight, fat free mass, and exercise performance [43,44]. A reasonable alternative would be guidance to optimize food selection to provide sufficient calories to meet basal energy expenditure and induce weight gain. As an example, oral nutrition supplements were assessed as part of a multimodal nutrition program in a trial that randomly assigned patients with oxygen-dependent COPD to take a 120 mL oral nutrition supplements (protein, carbohydrates, lipids at 20, 60, and 20 percent, respectively) three times daily for 90 days along with exercise and health education or to the health education component alone [45]. Body mass index (BMI), exercise tolerance, and quality of life (in females) improved, although the six-minute walk distance did not. Additional studies of efficacy are described below. (See 'Efficacy of nutritional support' below.)

For patients with mild to moderate lung disease, no particular commercial supplement is thought to be better than any other. For those with pulmonary cachexia, supplements with a 3:1 fat to carbohydrate ratio have been proposed because the respiratory quotient (ratio of carbon dioxide production to oxygen consumption) is 0.7 for fats and 1 for carbohydrates [46]. However, data in support of this increased fat to carbohydrate ratio are conflicting.

●Vitamin D – Studies of vitamin D supplementation in patients with COPD have not demonstrated a clear benefit [47-49]. In a one-year trial, 182 patients with moderate to severe COPD were randomly assigned to monthly injections of 100,000 IU of vitamin D or placebo [47]. No reduction was found in the incidence of exacerbations, hospitalizations, death, and no improvement occurred in FEV₁. In a subgroup analysis of this study, the effect of vitamin D on respiratory muscle function was assessed in patients who participated in pulmonary rehabilitation [48]. Compared with placebo, vitamin D supplementation was associated with a greater improvement in inspiratory muscle strength (-11 ± 12 cm H₂O versus 0 ± 14 cm H₂O; p = 0.004) and maximal oxygen uptake (110 ± 211 mL/min versus -20 ± 187 mL/min; p = 0.029), but no improvement in six-minute walk distance. A separate study of targeted medical nutrition (230 kcal; 2 g omega-3 fatty acids; 10 microg 25-hydroxy-vitamin D3) had positive effects on exercise-induced fatigue and dyspnea [50]. It should be noted that the level of vitamin D is decreased in states of inflammation. Thus, levels are likely not directly reflective of adequacy or deficiency in patients with COPD.

●Essential amino acids – Preliminary data from a small trial suggest that supplementation with essential amino acids (EAA) may be of benefit in patients with COPD. In a randomized, cross-over trial, supplements of free EAA were found to stimulate whole body protein anabolism more than supplements of free amino acids with the composition of complete proteins [51]. Whether this results in clinically relevant improvements is yet to be determined.

●Creatine supplements – Creatine supplements do not augment the training effect of pulmonary rehabilitation in patients with COPD [52].

●Antioxidant supplementation – In a randomized trial of 64 patients, antioxidant supplementation (eg, vitamins C and E, zinc, and selenium) provided to 64 patients with COPD during inpatient pulmonary rehabilitation failed to increase endurance (primary endpoint) compared with placebo but was associated with improved muscle strength [53]. Due to demonstrated harm in other patient groups [54] and little demonstrable benefit, we do not routinely supplement with antioxidants.

Efficacy of nutritional support — Nutritional support in COPD (eg, dietary advice, oral supplementation) modestly improves some clinically important outcomes such as six-minute walk test, inspiratory and expiratory muscle strength, quality of life, hand grip strength, and weight, but not mortality, spirometric values, or arterial blood gases [9,43]. Two meta-analyses have concluded that nutritional intervention in malnourished patients with COPD is effective in improving weight, body composition, and exercise performance [43,44]. However, nourished patients may not respond to the same degree.

●Mortality – A body weight less than 90 percent of ideal is an independent risk factor for mortality [55,56]. Additional data support a reduction in mean survival with those having an LBMI <17 for males or <14 for females [1]. However, there is no direct evidence that weight gain improves mortality.

●Weight – A meta-analysis of 11 trials that included 325 patients with malnutrition and COPD found a statistically significant weight gain with a mean difference of 1.65 kg (95% CI 0.14-3.16) among patients receiving oral supplementation instead of placebo [43].

●Lung function – A number of studies have examined the effect of nutritional support on lung function, with variable results [43,57-60]. In a meta-analysis of seven trials with 228 participants, there was no difference in the forced expiratory volume in one second (FEV₁) with supplementation [43]. The same analysis also examined changes in maximal inspiratory pressure (MIP) and maximal expiratory pressure (MEP) in malnourished patients (seven trials, 189 participants). Compared with placebo, those with supplementation had significantly better MIP (mean difference [MD] 5.02; 95% CI 0.29-9.76) and MEP (MD 12.73; 95% CI 4.91-20.55). When analyzing five trials with 142 participants, the six-minute walk distance did not increase significantly in the supplementation group [43]. While the pooled change from baseline was significant (MD 39.96 meters; 95% CI 22.66-57.26), it did not meet the minimal clinically important difference of 54 to 80 meters.

A multi-modality approach integrating a four-month interdisciplinary rehabilitation program and nutritional support (protein supplementation) improved BMI, fat-free mass, six-minute walk distance, and cycle endurance time in a randomized trial conducted in 39 patients with muscle-wasted COPD and moderate airflow obstruction [61]. The benefit persisted for 24 months.

●Quality of life – Studies of the effect of nutritional supplementation on quality of life have yielded mixed results. A meta-analysis pooled data from four trials that used two different instruments, the George's Respiratory Questionnaire (SGRQ) and the Chronic Respiratory Questionnaire (CRQ) [43], and found no significant difference in health-related quality of life with supplementation. When data from two trials using the SGRQ individual domains of activity, impact and symptoms were pooled, statistically and clinically significant improvements were noted with nutritional supplementation [43]. On the other hand, analysis of three trials that used individual domains from the CRQ (dyspnea, fatigue, emotion, mastery) found no significant difference between the nutrition and placebo groups.

Most studies, including those in the meta-analysis, evaluated the effects of nutritional supplementation after only several weeks to months of supplementation and did not stratify patients on the basis of their level of inflammation; therefore, the effect of long-term nutritional supplementation remains unknown.

Medications — For patients with pulmonary cachexia syndrome who are unable to increase their weight with the above interventions, we suggest medical therapy with the progesterone analog megestrol acetate. Some anabolic steroid treatments have also shown improvements in muscle mass in patients with COPD, but their potential adverse effects have led to withdrawal of regulatory approval in most countries. Both progesterone analogs and anabolic steroids have little or no effect on exercise capacity and may lead to adverse effects, so their efficacy in achieving weight gain should be assessed in individual patients and the medication discontinued in the absence of benefit.

●Progesterone analogs – The progesterone analog megestrol acetate may result in an increased appetite and improved caloric intake. In a randomized trial of 128 underweight (<95 percent ideal body weight) patients with COPD, megestrol acetate (800 mg orally once daily) was associated with a mean weight gain of 3.2 kg and increased appetite, while the placebo group had a weight gain of 0.7 kg [62]. There was no change in respiratory muscle function or exercise tolerance. The administration of megestrol acetate and its potential adverse effects are discussed separately. (See "Management of cancer anorexia/cachexia", section on 'Progesterone analogs'.)

●Anabolic steroids – Studies in COPD and other chronic wasting conditions indicate that anabolic steroids can specifically induce muscle gain [63]. In 82 underweight patients with COPD, the anabolic steroid oxandrolone (10 mg by mouth twice daily) was associated with a mean weight gain of 2.72 kg in two months, but no further gain at four months [64]. Adverse effects may include depression, hepatitis, peripheral edema, and virilization in females, which in combination has led to withdrawal of regulatory approval in the United States [65] and many other countries worldwide. (See "Management of cancer anorexia/cachexia", section on 'Androgens and selective androgen receptor modulators'.)

●Combination of megestrol and testosterone – In a small pilot study, combination therapy with daily megestrol and weekly testosterone injections in patients with pulmonary cachexia reversed the decline in involuntary weight loss and increased lean body mass [66].

EFFECT ON MORTALITY AND LUNG FUNCTION — The pulmonary cachexia syndrome is associated with an accelerated decline in functional status and can affect patients with any type of advanced lung disease, although it is best studied and described in association with chronic obstructive pulmonary disease (COPD) (see 'Definitions' above) [1,67]. As an example, cachexia is an independent predictor of mortality in patients with COPD [46,68-70]. Among patients with COPD who meet the definition of cachexia based on a low lean body mass index (BMI; <17 in males and <14 in females), median survival is reduced by almost half from about four to two years (figure 1) [68]. In a separate study of patients with advanced COPD requiring supplemental oxygen, survival decreased in correlation with BMI [69]. The effect of low BMI on survival is also reflected in the inclusion of a BMI ≤21 as a marker of more severe disease in the BODE index, which assesses mortality risk (calculator 3). (See "Chronic obstructive pulmonary disease: Prognostic factors and comorbid conditions", section on 'Prognostic factors'.)

Cachectic patients with COPD also have decreased diaphragm muscle mass, length, thickness, and strength (figure 2) [55,56]. This effect may be related to increased muscle breakdown due to catabolism [71]. In patients with COPD and a body weight within the normal range, diaphragm muscle mass, length, and thickness vary with body weight in a fashion similar to individuals with normal lung function.

Sarcopenia appears to be a risk factor for mortality in patients with idiopathic pulmonary fibrosis (IPF). In a study that assessed skeletal muscle mass in a cohort of 199 patients with IPF, the patients in the lowest quartile of cross-sectional area of erector spinae muscle experienced greater all-cause mortality (largely related to exacerbations of IPF) [72]. A separate study had similar findings for cross-sectional areas of other chest wall muscles normalized for stature [73].

Among patients without lung disease, carbon dioxide retention begins when respiratory muscle strength is <50 percent of normal and becomes marked when respiratory muscle strength is <25 to 35 percent of normal [74]. In patients with advanced lung disease, mechanical abnormalities (eg, airflow limitation in COPD, lung stiffness in pulmonary fibrosis) increase the work of breathing; therefore, hypercapnic respiratory failure occurs with lesser degrees of respiratory muscle weakness. Thus, malnutrition is associated with progressive diaphragmatic weakness and hypercapnic respiratory failure, an effect that is exacerbated in patients with advanced lung disease.

Low vitamin D levels are associated with reduced lung function [75,76]. A cross-sectional survey using data from the Third National Health and Nutrition Examination Survey that included 14,091 people found that the mean forced expiratory volume in one second (FEV₁) and mean forced vital capacity (FVC) were 126 and 172 mL greater, respectively, for the highest quintile of serum 25-hydroxy vitamin D level compared to the lowest quintile [75]. Vitamin D levels are influenced by serum levels of vitamin D binding protein (VDBP), which is a carrier protein for vitamin D with effects on macrophage activation and neutrophil chemotaxis [77]. The role of VDBP in lung health is under investigation [76,78]. As an example, serum VDBP is decreased in cystic fibrosis and levels correlate with poor nutritional status [79].

FUTURE DIRECTIONS

●Ghrelin – Ghrelin is a growth hormone (GH)-releasing peptide that induces a positive energy balance by decreasing fat utilization and stimulating feeding through GH-independent mechanisms. Some studies in cachectic patients with chronic obstructive pulmonary disease (COPD) suggest that repeated intravenous administration of ghrelin lessens muscle wasting and improves body composition, functional capacity, and sympathetic augmentation [80,81]. Ghrelin is not commercially available. (See "Ghrelin" and "Management of cancer anorexia/cachexia", section on 'Growth hormone and ghrelin analogs (anamorelin)'.)

●Anamorelin – Studies of anamorelin, an oral ghrelin mimetic, have been promising in treating malignancy associated anorexia, and additional studies in non-small cell lung cancer are in progress. Anamorelin is not commercially available. (See "Management of cancer anorexia/cachexia", section on 'Growth hormone and ghrelin analogs (anamorelin)'.)

●The role of inflammation – Studies in which patients with COPD are stratified by level of inflammation (to better understand the interaction between inflammation and nourishment) are needed.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chronic obstructive pulmonary disease" and "Society guideline links: Nutrition support (parenteral and enteral nutrition) in adults".)

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SUMMARY AND RECOMMENDATIONS

●Effect of malnutrition in lung disease – Malnutrition with loss of fat-free body mass in patients with advanced lung disease has been termed the pulmonary cachexia syndrome. Patients with pulmonary cachexia typically have weight loss and muscle wasting, although some patients have loss of fat-free body mass without weight loss. Pulmonary cachexia is associated with an accelerated decline in function and mortality. (See 'Definitions' above and 'Effect on mortality and lung function' above.)

●Definitions – The concepts of malnutrition, pulmonary cachexia, and sarcopenia are important to the understanding of muscle dysfunction in advanced lung disease. (See 'Definitions' above.)

•Malnutrition is a term that combines the impact of nourishment and catabolism, by merging elements from two sets of features: nonvolitional weight loss, low body mass index (BMI), or reduced muscle mass; and one or more of reduced food intake or underlying inflammation due to chronic disease or injury.

•Cachexia incorporates weight loss >5 percent in the last 12 months in addition to elements such as decreased muscle strength, fatigue, anorexia, low fat-free mass index (FFMI), increased inflammatory markers, anemia, and low serum albumin.

•Sarcopenia is defined as low skeletal muscle mass and reduced muscle function (eg, low handgrip strength or slow gait speed).

●Contributing factors – The pathogenesis of pulmonary cachexia is likely multifactorial, including changes in metabolism and caloric intake, aging, lack of exercise, tissue hypoxia, inflammation, medications, and possibly genetic predisposition. (See 'Contributing factors' above.)

●Diagnosis – The presence of pulmonary cachexia has traditionally been determined by a weight <90 percent of ideal body weight (calculator 1) or a BMI ≤20 (calculator 2). If advanced measures are available to calculate the lean body mass index (LBMI), the thresholds used are LBMI <17 in males and <14 in females. (See 'Evaluation and diagnosis' above.)

●Initial nutritional treatment strategies – For patients with malnutrition related to advanced lung disease, we provide guidance on optimizing food selection to allow for sufficient caloric intake to meet basal energy requirements and induce weight gain. Additionally, nutritional supplements have shown modest benefit in improving body weight, fat free mass, and exercise performance. Additional strategies to enhance caloric intake include eating small frequent meals with nutrient-dense foods (eg, liquid nutritional supplements), eating meals that require little preparation (eg, microwaveable), and resting before meals. (See 'Nutritional interventions' above.)

●Adjunctive exercise and pulmonary rehabilitation – Exercise has been shown to improve the effectiveness of nutritional therapy and to stimulate appetite. We encourage patients to participate in a pulmonary rehabilitation program to increase their exercise endurance. (See 'General measures for prevention and treatment' above and "Pulmonary rehabilitation".)

●Other general measures – In addition to enhanced nutrition and exercise, concomitant interventions include steps to reduce the work of breathing (eg, bronchodilators), improve oxygen delivery (eg, oxygen therapy), and control inflammation, if indicated (eg, inhaled glucocorticoids).

●Refractory cachexia – For patients with pulmonary cachexia who are unable to increase their weight with the above interventions, we suggest a trial of megestrol acetate (Grade 2C). Since progesterone analogs have little or no effect on exercise capacity and carry the potential for adverse effects, their efficacy in achieving weight gain should be assessed in individual patients and the medication discontinued in the absence of benefit. (See 'Medications' above and 'General measures for prevention and treatment' above.)