Review
J Nutr Health Aging.2022;26(7):723-731
Published online June 29, 2022, https://doi.org/10.1007/s12603-022-1822-8
A review on the Role of Oral Nutritional Supplements in Chronic Obstructive
Pulmonary Disease
W.-J. Huang1,2, X.-X. Fan1,2, Y.-H. Yang1,2, Y.-M. Zeng3,4, C.-Y. Ko1,2,3,4
1. Department of Clinical Nutrition, the Second Affiliated Hospital of Fujian Medical University, Quanzhou, China; 2. School of Public Health, Fujian Medical University, Fuzhou,
Fujian, China; 3. Department of Respiratory and Critical Care Medicine, the Second Affiliated Hospital of Fujian Medical University, Quanzhou, China; 4. Respiratory Medicine Center
of Fujian Province, Quanzhou, China.
Corresponding Author: Chih-Yuan Ko, The Second Affiliated Hospital of Fujian Medical University, No. 34, Zhongshanbei Rd, Licheng District, Quanzhou, Fujian Province, China,
362000. Tel.: +86 0595-26655200. E-mail address: yuanmomoko@gmail.com
Abstract
Due to the high smoking rate in developing countries and the rising
aging population in high-income countries, the global prevalence
of chronic obstructive pulmonary disease (COPD), estimated to be
11.7%, is increasing and is the third-leading cause of mortality. COPD
is likely to be present in elderly individuals with impaired gastro-
enteric functions. Gastrointestinal congestion, dyspnea, and anxiety
are pathophysiological characteristics of COPD, contributing to poor
appetite, reduced dietary intake, and high-energy expenditure. These
factors are implicated in the progression of malnutrition in COPD
patients. Malnutrition is detrimental to lung functions and is associated
with an increased risk of infection, exacerbation and mortality, and
a longer duration of hospitalization. Therefore, nutritional support
to treat malnutrition in COPD patients is very vital. Oral nutritional
supplements (ONS) may hold the key to COPD treatment. To clarify
this statement, we review current evidence for ONS in COPD patients
to benefit from clinical outcomes.
Key words: Chronic obstructive pulmonary disease (COPD), oral
nutritional supplements (ONS), aging, malnutrition.
C
Introduction
hronic obstructive pulmonary disease (COPD) is a
prevalent chronic respiratory disease characterized
by persistent airflow limitation and respiratory
symptoms. Large-scale epidemiological studies estimated the
number of COPD cases to be 384 million worldwide, with
a global prevalence of 11.7% in 2010 (1). The prevalence
of COPD is expected to increase in the next 40 years due to
continued exposure to risk factors and the aging population.
According to the World Health Organization, COPD accounted
for 3.1 million deaths in 2019, and was ranked as the third-
leading cause of death in the world (2). In 2018, the China
Pulmonary Health study estimated the number of COPD cases
to be approximately 100 million in China (3). Therefore, COPD
poses a significant burden on healthcare resources and has
become a public health crisis.
Generally, the prevalence of COPD is associated with
tobacco consumption, long-term exposure to air pollution, and
the aging population. COPD has a peak prevalence in people
aged >60 years. Patients with COPD have age-related impaired
sense of smell and taste and gastroenteric function, contributing
Received January 5, 2022
Accepted for publication June 12, 2022
© Serdi and Springer-Verlag International SAS, part of Springer Nature
to reduced dietary intake, weight loss, and malnutrition.
Malnutrition in COPD patients is associated with myophagism
manifesting as the atrophy of peripheral skeletal muscles
and diaphragm, affecting the inspiratory muscle strength.
Inspiratory muscle weakness could aggravate dyspnea, leading
to disease deterioration (4). The Global Initiative for Chronic
Obstructive Pulmonary Disease (GOLD) guidelines recommend
nutritional support for malnourished COPD patients. However,
the clinical significance of oral nutritional supplements (ONS)
in COPD patients is poorly understood. This review aims to
summarize recent evidence on whether ONS in COPD patients
has beneficial effects on clinical outcomes.
Literature search strategy
Two electronic databases, including PubMed and Web of
Science, were searched from January 1997 to May 2022. Search
items included chronic obstructive pulmonary disease, COPD,
oral nutritional supplement, ONS, nutritional supplement,
nutrition supplement, nutrient supplement, whey protein,
essential amino acids (EAAs), fatty acid, antioxidant, vitamin,
calcium, iron, magnesium, phosphorus, zinc, potassium,
sodium, chlorine, iodine, muscle, muscle atrophy, sarcopenia,
microRNA, miRNA and myomiR. The main outcomes were to
observe the role of ONS in regulating blood levels of protein
and inflammation, lung function, body composition, muscle
strength, physical performance, readmission, and mortality.
The selected references of reviews and original studies were
scrutinized to obtain further relevant evidence.
The role of ONS on blood biochemistry
Table 1 shows a summary of the research findings on how
different types of ONS influence blood biochemistry in COPD
patients. Total protein and serum albumin are useful indicators
of malnutrition in COPD patients (5). Hypoproteinemia or
hypoalbuminemia are considered risk factors for frequent
exacerbations of COPD and affect prognosis (6). Therefore,
therapeutic targets in COPD include preventing exacerbations
and improving patient prognosis. Several prospective
studies have confirmed that ONS could significantly elevate
or maintain serum levels of total protein, albumin, and
hemoglobin concentration (7-12).
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Table 1. A summary of research findings on effects of ONS on blood biochemistry in COPD patients
ONS types Intervention methods Subjects Samples Treatment Results References
Duration
Whole-nutrient ONS Intervention group: ONS (6.30 kJ/ml; CHO COPD patients whose 60 patients were 3 weeks Both groups showed an Cai et al. (7)
28.2%E, protein 16.7%E and fat 55.1%E) as part weight was <90% of the randomly assigned to two increase in total protein
of the diet ideal body weight groups after 3 weeks compared
Control group: High CHO diet (CHO 60.0- to the baseline
70.0%E, protein 15.0%E and fat 20.0-30.0%E),
total energy intake was similar to that of the
intervention group
EAAs EAAs group: Receiving 4 g/bid EAAs (22.90 COPD outpatients with EAAs group =44; 12 weeks There was a significant Dal Negro et
kJ/g) on the basis of daily dietary energy intake a BMI<23kg/m2 (GOLD placebo group =44 increase in serum al. (8)
of about 6652.60 kJ/d class 3-4) albumin in the EAAs
Placebo group: Receiving a placebo of 183.20 group
kJ per day on the basis of daily dietary energy
intake of about 6903.60 kJ/d
EAAs EAAs group: 4 g/bid EAAs Patients with stable 32 patients were 12 weeks EAAs significantly Dal Negro et
Control group: NR COPD (GOLD class 3-4) randomly assigned to elevated serum levels of al. (9)
EAAs or control group total protein and albumin
HP-HMB HP-HMB group: ONS bid (energy: 1464.40 COPD patients HP-HMB group =109; 90 days HP-HMB improved Deutz et al.
kJ/portion; CHO 50.0%E, protein 22.0%E, placebo group =105 the concentrations of (10)
fat 28.0%E, HMB 1.5 g/ portion and 26 other hemoglobin, serum
essential vitamins and minerals) calcium, and 25-hydroxy-
Placebo group: Placebo bid (energy: 200.80 kJ/ vitamin D
portion; CHO 100.0%E and vitamin C 10 mg/
portion, with no other macro/micronutrients)
Antioxidants Antioxidant group: PR combined with oral COPD patients Antioxidant group =32; 28 days The antioxidant group Gouzi et al. (11)
capsules containing antioxidant supplements placebo group =32 showed a significant
(α -tocopherol: 30 mg/d, ascorbate: 180 mg/d, increase in α-tocopherol/
zinc gluconate: 15 mg/d and selenomethionine: γ-tocopherol ratio, serum
50 μg/d) selenium, and total
Placebo group: PR combined with oral capsule protein compared to the
containing placebo control group
EPA Intervention group: 240 ml/d EPA-enriched ONS Hospitalized COPD Intervention group =24; NR During hospitalization, Ogasawara et
(5.23 kJ/ml; CHO 63.0%E, protein 20.0%E and patients with acute control group =21 the serum albumin al. (12)
fat 17.0% E) (240ml ONS containing 1.1g EPA, exacerbations or levels in the control
355 mg calcium and 4.1 μg vitamin D), total pneumonia group were significantly
energy intake (including ONS): 125.50-146.40 reduced, while those in
kJ/kg/d the EPA group remained
Control group: 250 ml/d ONS without EPA (6.28 unchanged
kJ/mL; CHO 54.5%E, protein 14.0%E and fat
31.5%) (250 ml ONS containing 0 g EPA, 200
mg calcium and 1.9 μg vitamin D), total energy
intake (including ONS): 125.50-146.40 kJ/kg/ d
n-3PUFAs Intervention group: 1673.60 kJ/d n-3PUFAs-rich COPD patients Sixty-four patients were 2 years There was a significant Matsuyama et
ONS (0.6 g n-3PUFAs, 0.4 g n-6PUFAs) randomly assigned to the decrease in serum and al. (14)
Control group: 1673.60 kJ/d n-3PUFAs-nonrich intervention or control sputum levels of LTB4,
ONS (0.07 g n-3PUFAs, 0.93 g n-6PUFAs) group TNF-α, and IL-8 in
the intervention group.
However, no significant
change was observed in
the control group
Magnesium citrate Intervention group: Receiving 300 mg/d Moderate to severe Intervention group =25; 6 months The control group Zanforlini et
magnesium citrate COPD patients with a control group =24 showed a significant al. (16)
Control group: Receiving a placebo containing BMI ranged from 18.6 to increase in serum
the same ingredients but no magnesium citrate 34.9 kg/m2 C-reactive protein
compared to the
intervention group
ONS enriched with Intervention group: Targeted medical nutrition Patients aged ≥50 ONS group =22; control 12 weeks The ONS group showed Calder et al.
vitamin D and n-3PUFAs bid (1924.80 kJ; 20 μg 25-hydroxy-vitamin D3, years with moderate to group =23 a decrease in serum (17)
20 g whey protein concentrate and minimum 4 severe COPD who were triglycerides and an
g n-3PUFAs) unwilling to lose weight increase in high-density
Control group: Isocaloric placebo bid (1673.60 or had a low BMI lipoprotein cholesterol
kJ; not containing 25-hydroxy-vitamin D3, compared with the
milk protein in place of pure whey protein and control group.
sunflower oil instead of n-3PUFAs-enriched
fish oil)
OPCs OPCs group:150 mg/d OPCs (given in Stable COPD patients OPCs group =13; placebo 8 weeks Supplementation with Lu et al. (18)
pharmaceutical form) group =14 OPCs effectively
Placebo group: The placebo had identical enhanced antioxidant
appearance to the OPCs supplement capacity and improved
blood lipid profile in
COPD patients
CHO: carbohydrate; %E: % of energy; EAAs: essential amino acids; BMI: body mass index; GOLD: the Global Initiative for COPD; NR: not reported; HP-HMB: high-protein ONS containing beta-
hydroxy-methylbutyrate; PR: pulmonary rehabilitation; EPA: eicosapentaenoic acid; n-3 PUFAs: n-3 polyunsaturated fatty acids; n-6 PUFAs: n-6 polyunsaturated fatty acids; LTB4: leukotriene B4;
TNF-α: tumor necrosis factor-; IL-8: interleukin-8; OPCs: oligomeric proanthocyanidins

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Table 2. A summary of research findings on effects of ONS on lung functions in COPD patients
ONS types Intervention methods Subjects Samples Treatment Results References
Duration
Whole-nutrient ONS Group 1: Consumption of two or more COPD patients with Icelandic Group 1=13; group 2=10 12 months From baseline to the Ingadottir et al.
flavors and pack sizes of ONS per day Simple Screening (ISS) score end of the intervention, (20)
(2510.40 kJ/d energy and about 22 g/d ≥4 SGRQ scores in two
protein from ONS, total energy intake was groups were significantly
significantly higher than baseline) reduced
Group 2: Consumption of two or more
alternative snacks per day (2510.40
kJ/d energy and about 22 g/d protein
from snacks, total energy intake was
significantly higher than baseline)
Whole-nutrient ONS Intervention group: Daily diet plus ONS COPD patients Intervention group=14; 2 weeks The FVC of the Saudny-
(energy intake about 163.20 kJ/kg/d) control group=10 intervention group Unterberger et
Control group: Daily diet (energy intake improved but not in the al. (21)
about 121.30 kJ/kg/d) control group
EAAs EAAs group: Receiving 4 g/bid EAAs COPD outpatients with EAAs group=44; placebo 12 weeks Significant improvement Dal Negro et
(22.90 kJ/g) on the basis of daily dietary BMI<23 kg/m2 (GOLD class group=44 in the SGRQ scores was al. (8)
energy intake of about 6652.60 kJ/d 3-4) observed only in patients
Placebo group: Receiving a placebo of of the EAAs group
183.20 kJ per day on the basis of daily
dietary energy intake of about 6903.60
kJ/d
Whey drinks enriched Intervention group: Receiving 250 ml/d Male patients with moderate to Intervention group=23; 8 weeks The scores of SGRQ in Ahmadi et al.
with vitamin C and whey drink (1.90 kJ/ml; containing 275 severe COPD control group=23 the intervention group (23)
magnesium mg magnesium, 685 mg vitamin C and improved significantly
15.9 g whey protein), dietary advice and
daily care
Control group:Dietary guidance and
routine care
ONS enriched with Intervention group: Targeted medical Patients aged ≥50 years with ONS group =22; control 12 weeks The Borg scores assessed Calder et al.
vitamin D and n-3PUFAs nutrition bid (1924.80 kJ; 20 μg moderate to severe COPD who group =23 dyspnea in the ONS (17)
25-hydroxy-vitamin D3, 20 g whey protein were unwilling to lose weight group was significantly
concentrate and minimum 4 g n-3PUFAs) or had a low BMI lower compared with the
Control group: Isocaloric placebo bid control group
(1673.60 kJ; not containing 25-hydroxy-
vitamin D3, milk protein in place of pure
whey protein and sunflower oil instead of
n-3PUFAs-enriched fish oil)
SGRQ: St. George’s Respiratory Questionnaire; FVC: forced vital capacity; EAAs: essential amino acids; BMI: body mass index; GOLD: the Global Initiative for COPD; n-3PUFAs: n-3 polyunsaturated
fatty acids

COPD is a respiratory disease associated with chronic airway
inflammation and increasing inflammatory mediators involved
in the pathogenesis of COPD. Therefore, therapeutic targets
in COPD include reducing the inflammatory response. N-3
polyunsaturated fatty acids (n-3 PUFAs) have been identified
as «anti-inflammatory agents « (13). A study has shown that
n-3 PUFAs significantly decreased the serum and sputum levels
of leukotriene B4 (LTB4), tumor necrosis factor-α (TNF-α),
and interleukin (IL)-8 in COPD patients (14). However, only a
few studies have explored the anti-inflammatory effects of n-3
PUFAs in COPD (15). Moreover, a double-blind randomized
controlled trial (RCT) supported the possible anti-inflammatory
role of oral magnesium supplementation in COPD patients
[16]. ONS comprising of vitamin D, n-3 PUFAs, or oligomeric
proanthocyanidin was shown to improve the lipid profile in
COPD patients (17, 18).
The role of ONS on lung function
COPD is a progressive and systemic disorder characterized
by high-energy catabolism attributed to an imbalance in protein
synthesis and catabolism (19). The major hallmarks of COPD
include decreased pulmonary function due to inspiratory muscle
loss, leading to inspiratory muscle weakness, low pulmonary
performance, and insufficient pulmonary ventilation. Table 2
shows a summary of the research findings on how different
types of ONS influence lung function in COPD patients.
COPD patients may have high nutritional requirements due
to insufficient dietary intake as a result of dyspnea or due to the
high-energy expenditure. Therefore, ONS may be given to meet
the additional nutritional needs. Patients with COPD have high
requirements of nutrients, especially that of EAAs (8), the basic
building blocks of proteins. EAAs enhance protein synthesis
and stimulate muscle growth, consequently alleviating dyspnea
in patients (20, 21). The activation of the ubiquitin-proteasome
pathway mediates protein degradation in COPD patients by
increasing the production of reactive oxygen species (22).
Antioxidants mop up reactive oxygen species and thus could
protect COPD patients from oxidative stress. Consequently,
antioxidants may improve lung function, leading to increased
forced expiratory volume in the first second (FEV1) and forced
vital capacity (FVC). A previous study showed that vitamin
C-enriched whey protein ONS was associated with consistent
improvement in lung function and the St. George’s Respiratory
Questionnaire (SGRQ) scores in COPD patients (23). Further,
a metabolomics study analyzing 82 patients with severe COPD
showed that the serum metabolites of n-3 PUFAs, such as
eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA),
were negatively correlated with FEV1/FVC (24). In addition,
another previous study showed that consuming ONS composed

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of n-3 PUFAs could reduce the Borg scores assessed dyspnea
and post-walk fatigue to some extent (17).
The role of ONS on body composition
The body composition is measured using bioelectrical
impedance analysis (BIA), dual-energy x-ray absorptiometry
(DEXA), magnetic resonance imaging (MRI), or other body
composition analysis techniques. Measurement of body
composition determines body mass index (BMI), fat mass
(FM), fat-free mass (FFM), fat-free mass index (FFMI), protein,
and the body mineral content (25, 26). Body composition
analysis techniques are clinically valuable in evaluating the
nutritional risk (27) and the effectiveness of ONS in improving
nutritional support.
Table 3 shows a summary of the research findings on how
different types of ONS influence the body composition in
COPD patients. The body weight and FFM can be increased
by adding supplemental nutrition therapy to exercise training.
Although regular pulmonary rehabilitation training effectively
alleviates dyspnea, improves exercise endurance and health-
related quality of life, incorporating ONS into pulmonary
rehabilitation could be more beneficial in enhancing the
body composition of COPD patients (28). ONS can meet
the energy demand during pulmonary rehabilitation training,
thus overcoming the energy imbalance. Seven RCTs in a
systematic analysis revealed that the body weight of patients
was significantly higher in the ONS intervention group than
in the placebo group. Further, another three RCTs showed
a significant increase in FFM in patients treated with ONS
compared with placebo (29).
Although sufficient nutritional supplementation in
COPD patients prevents deterioration of physical function
and promotes recovery, the ONS should be taken in the
recommended dosage to prevent excessive energy intake,
which could exacerbate hypoxia (24, 30, 31). A previous study
evaluating ONS dosage in two groups of patients receiving
similar macronutrient composition: group A (three portions of
ONS daily; 125ml per serving, 6.35kJ/ml) and group B (three
portions of ONS daily; 200ml per serving, 4.19kJ/ml) revealed
that group A, which received less energy, recorded a higher
weight-gain than group B. The FFM and FM increased by a
ratio of 2:1 in both groups (30).
In addition to whole-nutrient ONS, single-nutrient ONS
like EAAs or combined-nutrient ONS, such as high-protein
ONS fortified with beta-hydroxy-methylbutyrate (HP-HMB),
ONS containing leucine, vitamin D and PUFAs, or whey
drinks enriched with vitamin C and magnesium were shown to
significantly improve body weight and FFMI in COPD patients
(8, 23, 32-34). These results indicate that ONS is beneficial in
improving body composition in COPD patients. Further studies
are needed to determine situations where it is more efficient,
optimal dosage and nutrient ratio of ONS in COPD.
The role of ONS on sarcopenia
COPD is known as a complex syndrome not only involving
the lungs but also the whole body. For instance, patients with
726
advanced COPD tend to have muscle atrophy. COPD may
complicate in sarcopenia, thus aggravating dyspnea, and
impairing exercise capacity (35). The Asian Working Group
for Sarcopenia (AWGS) 2019 consensus defined sarcopenia as
«the loss of lean mass and muscle strength and/or low physical
performance associated with aging» (36). Sarcopenia is a
progressive and extensive skeletal muscle disease. Sarcopenia
has a reported prevalence in COPD patients of 21.6% (37).
Exacerbations in COPD adversely affect muscle tissue and the
physical performance measured by handgrip strength, balance,
gait speed, and daily activity tests (38). However, the muscle is
capable of self-repair. Muscle-specific microRNAs (myomiRs)
modulate muscle regeneration following injury via targeting
different signaling pathways (39).
The role of ONS on lean mass, muscle strength,
and physical performance
Several factors contribute to sarcopenia frailty syndrome.
However, nutritional intervention improves lean mass and
physical function (40). Previous observational studies revealed
that high-quality protein, vitamin D, antioxidants, and PUFAs
are beneficial nutrients in muscle regeneration (41, 42). Table
4 shows a summary of the research findings on how different
types of ONS influence lean mass, muscle strength, and
physical performance in COPD patients. ONS is widely used in
clinical therapeutics as a nutritional formula providing various
nutrients, thus improving body weight and FFM in COPD
patients. A large RCT conducted in the United States, the
Nutrition Effect on Unplanned Readmissions and Survival in
Hospitalized Patients (NOURISH) study, found that HP-HMB
could prevent or attenuate muscle wasting in COPD patients
and significantly improve the body weight (10) and handgrip
strength (10, 43). Other studies revealed that ONS containing
antioxidants (vitamins C, vitamins E, zinc, and selenium) or
vitamin B12 showed significant positive effects on muscle
strength (11, 44). Therefore, it is hypothesized that ONS could
ameliorate the muscle damage caused by oxidative stress in
COPD patients.
Assessment for COPD patients’ physical performance
includes a six-minute walking test, chair-stand test, short
physical performance battery (SPPB), and activities of daily
living (ADL) score (45). Eighty-one outpatients with COPD
were randomized to receive ONS containing high doses of
leucine, vitamin D, and n-3 PUFAs or placebo over four
months. The study revealed that the number of daily steps in the
ONS group was significantly higher than in the placebo group
(34, 46). Another 12-week trial, including 88 advanced COPD
outpatients with BMI<23kg/m2, reported that ONS containing
EAAs significantly increased the average number of daily steps
walked in one week (8).
The role of ONS on myomiRs
MyomiRs, known as muscle-derived microRNAs, are
members of the non-coding RNAs group. MyomiRs are
effective regulators in muscle proliferation, differentiation,
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Table 3. A summary of research findings on effects of ONS on body composition in COPD patients
ONS types Intervention methods Subjects Samples Treatment Results References
Duration
Whole-nutrient ONS Group A: 125 mL ONS tid (6.35 kJ/ml; Stable COPD Group A=19; group B=20 8 weeks FFM and FM increased by a Broekhuizen
CHO 60.0%E, protein 20.0%E and fat ratio of 2:1 in both groups, et al. (30)
20.0%E) but the weight gain in group
Group B: 200 mL ONS tid (4.19 kJ/ml; A was higher compared to
CHO 59.7%E, protein 22.3%E and fat group B.
18.0 %E)
Whole-nutrient ONS PRNS group: PR plus 250 ml ONS tid Advanced COPD PRNS group=15; PR 8 weeks Nutritional supplement Gurgun et al.
(energy: NR; CHO 53.3%E, protein group=15; control incorporated of PR can make (28)
16.7%E and fat 30.0%E) group=16 more benefit in terms of lean
PR group: PR mass
Control group: Routine care
ONS enriched with 125 ml ONS enriched with antioxidant COPD patients with Group A=14; group B=10 12 weeks Group A exhibited an increase Planas et al.
antioxidant [6.28 kJ/mL; CHO 60.0%E and protein BMI≤22 kg/m2, in body weight, triceps (31)
20.0%E (whey protein/casein ratio: FFMI≤16 kg/m2 and/or skinfold thickness and FM,
50/50)]. Additional ONS on the basis of recent weight loss but a decrease in FFMI.
daily diet resulted in REE*1.7 in group A Group B exhibited an increase
and REE*1.3 in group B. in body weight and handgrip
strength.
EAAs EAAs group: Receiving 4 g/bid EAAs COPD outpatients with EAAs group =44; 12 weeks EAAs improved FFM Dal Negro et
(22.90 kJ/g) on the basis of daily dietary a BMI<23kg/m2 (GOLD placebo group =44 al. (8)
energy intake of about 6652.60 kJ/d class 3-4)
Placebo group: Receiving a placebo of
183.20 kJ per day on the basis of daily
dietary energy intake of about 6903.60
kJ/d
EAAs EAAs group: PR combined with 4 g/d COPD patients with EAAs group=14; control 12 weeks Body weight and FFM Baldi et al.
EAAs supplementation (total protein weight lost >5% over the group=14 increased in both groups, (32)
intake in ONS and daily diet reached last 6 months but the increase was more
1.5-1.7 g/kg/d, total energy intake 7937.0 significant in the EAAs group
kJ/d) compared to control group
Control group: PR (total energy intake in
daily diet reached 7598.1 kJ/d)
HP-HMB HP-HMB group: ONS bid (energy: Malnourished elderly HP-HMB group=328; 90 days Body weight at day 30 was Deutz et al.
1464.40 kJ/portion; CHO 50.0%E, patients with congestive Placebo group=324 higher in HP-HMB group (33)
protein 22.0%E, fat 28.0%E, HMB 1.5 g/ heart failure, acute than in the placebo group
portion and 26 other essential vitamins myocardial infarction,
and minerals) pneumonia or COPD
Placebo group: Placebo bid (energy:
200.80 kJ/portion; CHO 100.0%E and
vitamin C 10 mg/portion, with no other
macro/micronutrients)
ONS enriched with Intervention group: Exercise training COPD patients with Intervention group=42; 12 months Overall weight, muscle van Beers et
leucine, vitamin D and plus ONS tid (6.275kJ/ml; CHO 60.0%E, moderate airflow placebo group=39 mass, and fat mass showed al. (34)
n-3PUFAs protein 20.0%E, fat 20.0%E and mi- restriction and impaired a decreasing trend in the
cronutrients, and enriched with leucine, exercise performance placebo group, but an
vitamin D and n-3 PUFAs) increasing trend in the
Placebo group: Exercise training plus no- intervention group
calorie flavored drinks tid
Whey drinks enriched Intervention group: Receiving 250 ml/d Male patients with Intervention group=23; 8 weeks FFMI and body protein levels Ahmadi et al.
with vitamin C and whey drink (1.90 kJ/ml; containing 275 moderate to severe control group=23 were significantly increased in [23]
magnesium mg magnesium, 685 mg vitamin C and COPD the intervention group
15.9 g whey protein), dietary advice and
daily care
Control group: Dietary guidance and
routine care
CHO: carbohydrate; %E: % of energy; FFM: fat free mass; FM: fat mass; PRNS: nutritional supplementation with pulmonary rehabilitation; PR: pulmonary rehabilitation; NR: not reported; REE:
resting energy expenditure; BMI: body mass index; FFMI: fat free mass index; EAAs: essential amino acids; GOLD: the Global Initiative for COPD; HP-HMB: high-protein ONS containing beta-
hydroxy-methylbutyrate; n-3 PUFA: n-3 polyunsaturated fatty acids

and regeneration (47, 48). Multiple studies comparing the
levels of myomiRs (miR-l, miR-23a, miR-27a, miR-133,
miR-203, miR-206, and miR-499) (Table 5) in the serum,
plasma, and muscle tissues obtained from healthy people and
COPD patients, revealed that COPD patients, even when in a
stable condition had higher levels of myomiRs than healthy
subjects (49-54). This finding suggests that the change in
myomiRs as molecular markers of muscle damage was
considered as a negative feedback regulation to repair damaged
muscle tissue. Sarcopenia was originally used to describe
the decrease in lean mass among the elderly (55). Studies
conducted in elderly patients with sarcopenia revealed that
the expression of myomiRs was upregulated after consuming
leucine-enriched ONS. This finding suggests that nutritional
intervention is a potential strategy for counteracting age-related
muscle dysfunction (56, 57). However, there is no literature
available reporting the changes in expression of myomiRs in
COPD patients after dietary or ONS intervention. Therefore,
prospective studies of ONS in COPD patients need to be carried
out to determine whether myomiRs are potential molecular
targets.

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Table 4. A summary of research findings on effects of ONS on lean mass, muscle strength and physical performance in COPD
patients
ONS types Intervention methods Subjects Samples Treatment Results References
Duration
HP-HMB HP-HMB group: ONS bid (energy: 1464.40 COPD patients HP-HMB group =109; 90 days HP-HMB Deutz et al. (10)
kJ/portion; CHO 50.0%E, protein 22.0%E, placebo group =105 supplementation
fat 28.0%E, HMB 1.5 g/ portion and 26 other increased handgrip
essential vitamins and minerals) strength and body weight
Placebo group: Placebo bid (energy: 200.80 kJ/
portion; CHO 100.0%E and vitamin C 10 mg/
portion, with no other macro/micronutrients)
HP-HMB HP-HMB group: ONS bid (energy: 1464.40 Malnourished elderly HP-HMB group=328; 90 days Handgrip strength was Matheson et al.
kJ/portion; CHO 50.0%E, protein 22.0%E, patients with congestive placebo group=324 significantly higher in (43)
fat 28.0%E, HMB 1.5 g/ portion and 26 other heart failure, acute HP-HMB group than in
essential vitamins and minerals) myocardial infarction, the placebo group
Placebo group: Placebo bid (energy: 200.80 kJ/ pneumonia or COPD
portion; CHO 100.0%E and vitamin C 10 mg/
portion, with no other macro/micronutrients)
Antioxidants Antioxidant group: PR combined with oral COPD patients Antioxidant group =32; 28 days The muscle strength was Gouzi et al. (11)
capsules containing antioxidant supplements placebo group =32 significantly greater in
(α -tocopherol: 30 mg/d, ascorbate: 180 mg/d, antioxidant group than in
zinc gluconate: 15 mg/d and selenomethionine: the placebo group
50 μg/d)
Placebo group: PR combined with oral capsule
containing placebo
Vitamin B12 Intervention group:500 mg/d vitamin B12 Patients with moderate to Rehabilitation group=8; 8 weeks Vitamin B12 Paulin et al. (44)
Placebo group: maltodextrin severe COPD rehabilitation plus supplementation had a
vitamin B12 group =8; positive effect on exercise
vitamin B12 group=8; tolerance in COPD
placebo group =8 patients
ONS enriched with Intervention group: Exercise training plus COPD patients with Intervention group=42; 12 months The physical performance van Beers et al.
leucine, vitamin D and ONS tid (6.275kJ/ml; CHO 60.0%E, protein moderate airflow placebo group=39 of the placebo group was (34)
n-3PUFAs 20.0%E, fat 20.0%E and micronutrients, and restriction and impaired significantly reduced, but
enriched with leucine, vitamin D and n-3 exercise performance was unchanged in the
PUFAs) intervention group
Placebo group: Exercise training plus no-
calorie flavored drinks tid
ONS enriched with ONS group: 250 or 375 ml/d ONS (6.275 kJ/ COPD patients with low Eighty-one patients were 4 months ONS optimized the van de Bool et
leucine, vitamin D and ml; CHO 60.0%E, protein 20.0%E, fat 20.0%E muscle mass randomized to ONS nutritional status of al. (46)
n-3PUFAs and enriched with leucine, vitamin D and group or placebo group patients and positively
n-3PUFAs) improved physical
Placebo group: 250 or 375 ml /d calorie-free activity
flavored drinks
EAAs EAAs group: Receiving 4 g/bid EAAs (22.90 COPD outpatients with EAAs group =44: 12 weeks Oral supplementation Dal Negro et
kJ/g) on the basis of daily dietary energy intake a BMI<23kg/m2 (GOLD placebo group =44 of EAAs improved al. (8)
of about 6652.60 kJ/d class 3-4) the nutritional status
Placebo group: Receiving a placebo of 183.20 and quality of life and
kJ per day on the basis of daily dietary energy enhanced muscle strength
intake of about 6903.60 kJ/d in COPD patients
HP-HMB: high-protein ONS containing beta-hydroxy-methylbutyrate; CHO: carbohydrate; %E: % of energy; PR: pulmonary rehabilitation; n-3 PUFA: n-3 polyunsaturated fatty acids; EAAs: essential
amino acids; BMI: body mass index; GOLD: the Global Initiative for COPD

The role of ONS on readmission and mortality
One of the most important clinical manifestations of
nutritional deficiency in COPD patients is physical dysfunction
related to loss of lean mass. However, inadequate nutrition
will also impair immune function, leading to an increased risk
of infection, disease deterioration, hospital admissions, and
even death. The European Society for Clinical Nutrition and
Metabolism (ESPEN) reported that malnourishment contributes
to a four-fold increase in the risk of mortality in COPD patients
within two years. Low FFMI or BMI was reported to be
independent predictor of increased risk of death in COPD
patients (58). Therefore, preventing and managing malnutrition
in COPD patients is paramount to reducing readmission rates
and mortality.
Table 6 shows a summary of the research findings on how
different types of ONS influence readmission and mortality
rates in COPD patients. HMB is a leucine metabolite that
regulates protein synthesis during muscle growth, leading to
increased muscle mass and strength (59), as well as improving
overall survival (10, 33). A multi-center and high-quality RCT
showed that addressing vitamin D deficiency in COPD patients
ameliorated disease deterioration (60), possibly by reducing
chronic airway and systemic inflammation and increasing
bacterial clearance, thus decreasing susceptibility to infections
and exacerbations (61). Furthermore, several observational
studies have shown that serum level of magnesium was a
significant predictor of worsening symptom in COPD patients
(62-64). However, the role of oral magnesium supplementation
on exacerbation in COPD patients remains unconfirmed.
Conclusion
COPD is highly prevalent in the older population. COPD
patients have high acute episode, readmission and mortality
rates, and poor health-related quality of life. Insufficient

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Table 5. The expression level of MyomiRs in COPD patients

Samples Material MyomiRs Results References
COPD group=103; control group =25 Plasma MiR-1; miR-133; miR-203; The expression level of MyomiRs in the plasma Donaldson et al. (49)
miR-206; miR-499 of COPD patients was elevated
Smoking COPD group=17; non-smoking group=15 Peripheral whole blood MiR-203 The expression of miR-203 in COPD patients Shi et al. (50)
was significantly higher than in non-smokers
COPD group=41; control group=19 Vastus lateralis MiR-1; miR-27a; miR-206 MyomiRs expression was elevated in COPD Puig-Vilanova et al. (51)
patients
COPD group=29; healthy control group=10 Vastus lateralis MiR-1; miR-206 The expression levels of miR-1 and miR-206 in Barreiro et al. (52)
the vastus lateralis of the patients was higher than
in control group
Stable COPD group =13; sedentary control group =13 Vastus lateralis MiR-1 The expression of miR-1 was higher in the vastus Puig-Vilanova et al. (53)
lateralis of COPD patients compared with the
control group
COPD group =46; non-smoking control group=34 Plasma MiR-1; miR-23a High-throughput sequencing revealed Shen et al. (54)
differentially expressed microRNAs in plasma
between the two groups, in which miR-23a and
miR-1 were up-regulated in COPD patients

Table 6. A summary of research findings on effects of ONS on readmission and mortality in COPD patients
ONS types Intervention methods Subjects Samples Treatment Results References
Duration
HP-HMB HP-HMB group: ONS bid (energy: 1464.40 kJ/ COPD patients HP-HMB group =109; 90 days The HP-HMB group had a Deutz et al. (10)
portion; CHO 50.0%E, protein 22.0%E, fat 28.0%E, placebo group =105 higher overall survival rate
HMB 1.5 g/portion and 26 other essential vitamins compared with the placebo
and minerals) group
Placebo group: Placebo bid (energy: 200.80 kJ/
portion; CHO 100.0%E and vitamin C 10 mg/
portion, with no other macro/micronutrients)
HP-HMB HP-HMB group: ONS bid (energy: 1464.40 kJ/ Malnourished elderly patients HP-HMB group=328; 90 days The 90-day mortality was Deutz et al. (33)
portion; CHO 50.0%E, protein 22.0%E, fat 28.0%E, with congestive heart failure, placebo group=324 significantly lower in the HP-
HMB 1.5 g/portion and 26 other essential vitamins acute myocardial infarction, HMB group compared with
and minerals) pneumonia or COPD the placebo group
Placebo group: Placebo bid (energy: 200.80 kJ/
portion; CHO 100.0%E and vitamin C 10 mg/
portion, with no other macro/micronutrients)
Vitamin D Vitamin D group: 6 ml/d Vigantol oil (containing 3 COPD patients Vitamin D group=122; 1 year Vitamin D3 supplementation Martineau et
mg vitamin D3) placebo group =118 reduced the risk of disease al. (60)
Placebo group: 6 ml/d of sensory identical placebo deterioration and hospital
readmissions
Vitamin D Group A: 2000 IU/d vitamin D COPD patients Group A=60; group B=60 6 months Vitamin D significantly Khan et al. (61)
Group B: No intervention reduced the susceptibility
to exacerbation and the
readmission rate
HP-HMB: high-protein ONS containing beta-hydroxy-methylbutyrate; CHO: carbohydrate; %E: % of energy

dietary intake, chronic inflammation, tissue hypoxia, loss of presents recent evidence on the beneficial effects of ONS on
lean mass, and increased resting metabolic rate contribute to COPD patients and discusses future research gaps.
malnutrition in COPD patients. Malnutrition is common in
COPD, significantly influences disease progression, and is Conflicts of interest: The authors declare that no financial conflicts of interest exist.

linked to poor clinical outcomes. Therefore, nutritional support

is required to manage FFM depletion, and improve physical
function and overall quality of life.
This review aims to present the benefits of ONS for COPD
patients. ONS optimizes the nutritional status, increases body
weight and FFM, improves muscle strength and physical
function, enhances inspiratory muscle strength, alleviates
dyspnea, increases total protein concentration, and reduces
the inflammatory response, leading to improved quality of life
and overall survival in COPD patients. However, it has worth-
mentioning limitations. First, the specific requirements of each
nutrient in the ONS in COPD patients were not summarized.
Second, the role of ONS in improving common clinical status,
such as heart failure and serum electrolyte imbalance, in COPD
patients was not summarized. Taken together, this review
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How to cite this article: W.-J. Huang, X.-X. Fan, Y.-H. Yang, et al. A review on the Role
of Oral Nutritional Supplements in Chronic Obstructive Pulmonary Disease. J Nutr
Health Aging.2022;26(7):723-731; https://doi.org/10.1007/s12603-022-1822-8