Initial results of using mesenchymal stem cell and platelet rich plasma in treatment of chronic obstructive pulmonary disease

Journal of military pharmaco-medicine no8-2019

INITIAL RESULTS OF USING MESENCHYMAL STEM CELL
AND PLATELET RICH PLASMA IN TREATMENT
OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE
Dao Ngoc Bang1; Dong Khac Hung2; Nguyen Huy Luc1
Do Minh Trung2; Ta Ba Thang1; Le Phuong Ha3
SUMMARY
Objectives: To assess initial results and the safety of stem cell and platelet rich plasma in
treatment of chronic obstructive pulmonary disease. Subjects and methods: This interventional
trial was carried out on 10 chronic obstructive pulmonary disease patients, with the number of
patients of group C and D were 2 and 8, respectively, following to GOLD 2018. Mesenchymal
stem cells were taken from the umbilical cord tissue of pregnant women, were given
intravenously to patients with the dose of 1.5 milion cells per kilogram in combination with
5 mililiters of self-platelet rich plasma. These patients were followed up within 6 months.
Results: Clinical and para-clinical indexes improved after 6 months of treatment: mMRC score
decreased from 3 to 2, CAT score went from 22 down to 20 and CRP reduced from 5.12 to 2.68
miligram per deciliter. There was no severe complication. Conclusions: The combination of
mesenchymal stem cells and platelet rich plasma is a method with its first effectiveness and
safety in treatment of severe chronic obstructive pulmonary disease patients. With these initial
results, the following studies are expected to carry out to assess the role of mesenchymal stem
cells and platelet rich plasma in treatment of chronic obstructive pulmonary disease patients.
* Keywords: Chronic obstructive pulmonary disease; Mesenchymal stem cell; Platelet rich plasma.

INTRODUCTION
Chronic obstructive pulmonary disease
(COPD) is now a global burden of disease
with high mortality. Many theories about
COPD pathogenesis have been mentioned,
in which the inflammatory mechanism
was recognized by many authors [1, 3].

Till now, many studies have proved that
the effectiveness of mesenchymal stem cells
(MSCs) in treatment of anti-inflammatory
proccess, increase in immune ability and
regeneration of tissue. Therefore, MSCs
have been studied in treatment of COPD

in order to improve pulmonary fibrosis,
reduction of pulmonary arterial pressure
and anti-inflammation. Besides, platelet rich
plasma (PLT) contains growth factors,
helping regeneration of tissue. With the
combination with PLT, MSCs work effectively
[4, 5, 6]. In Vietnam, this combination has
been firstly applied in treatment of COPD
patients. By this reason, this study was
carried out with the aim: To assess initial
results and the safety of stem cell and
platelet rich plasma in treatment of chronic
obstructive pulmonary disease.

1. 103 Military Hospital
2. Vietnam Military Medical University
3. University of Science and Technology of Hanoi
Corresponding author: Dao Ngoc Bang ()
Dtae received: 29/07/2019
Date accepted: 15/10/2019

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Journal of military pharmaco-medicine no8-2019
SUBJECTS AND METHODS
1. Subjects.
10 patients diagnosed with COPD,
having indications of treatment by MSCs
and PLT, treated in Respiratory Center,
103 Military Hospital from Jul 2018 to Apr
2019.
* Patient selection criteria: Defined
stable COPD group C and D according to
GOLD standard (2018) [1]. These patients
were voluntary to attend in the study.
* Patient exclusion criteria: Patients
had other respiratory diseases, severe codiseases (such as: heart failure, kidney
failure and so on), other diseases related
to tumour, contrindications of respiratory
functional measurement.
2. Methods.
* Study design:
This is a clinical non-controlled trial
with vertical follow-up. Patients underwent
clinical examination, tests of biochemical
blood and blood cells to assess function
of organs, tumour markers, ECG and
cardiosonography,
chest
X-ray,
measurement of spirometer and
plethymosgraphy, arterial blood gases

test before treatment of MSCs and PLT.
Patients underwent treatment by MSCs
and self-PLT based on the process,
accepted by the Ethics Committee of
Vietnam Ministry of Health. These patients
were taken sellf-blood to separate PLT.
Then, 5 mL of PLT were mixed with MSCs,
taken from the umbilical cord tissue, with
the dose of 1.5 million of MSCs per
kilogram. This combination was mixed
with 100 mL of NaCl 0.9% and given

intravenously to patients with the speed
of 3.5 mL per minute. Definition of clinical
results, blood cells, CRP and changes of
respiratory function of these patients.
They were re-examined by the time of
1, 3 and 6 months after treament. By each
time, they were defined: changes of clinical
symptoms (level of dyspnea based on
mMRC scale, CAT and SMWD), number
of white blood cells with the proportions of
neutrophil and lymphocyte, CRP, indexes
of spirometer, such as: force vital capacity
(FVC), force expiratory volume in the
1st second (FEV1), arterial blood gases indexes,
such as: oxygen arterial preasure (PaO2),
carbondioxite arterial preasure (PaCO2).
Early complications (within 1 week) and
late ones (within 6 months after treament).

All studied patients underwent internal
treatment regularly based on Guidelines
of Vietnam Ministry of Health (2018) [1].
Management and statistical analysis
was performed by the SPSS 20.0 software.
RESULTS AND DISCUSSION
1. Characteristics of studied patients.
* Characteristics of age and gender:
100% of studied patients were male,
with the average age of 67.9 ± 6.47 years
old and 60% belonged to group of 60 70 years old, only 10% of patients at
the age under 60 years old. These
characteristics of age and gender were
similar to other studies about COPD in
Vietnam. Hoaang Dinh Huu Hanh and Le
Thi Tuyet Lan (2008) witnessed that the
average age of COPD patients was 63 ±
11.97 years old, with 87% belonged to
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Journal of military pharmaco-medicine no8-2019
male [2]. However, the number of female
patients was lower than that in other studies
in the world. Weiss D.J et al (2013)

treated stem cells for 30 COPD patients,
having the average age of 68.1 ± 7.54
years old, with the proportion of 60% [8].

Table 1: Clinical characteristics of studied patients before treatment.
Value

X ± SD

Min

Max

Age (years old)

67.9 ± 6.47

58

77

Pack-year

12.2 ± 11.11

10

40

19 ± 9.66

3

40

BMI (kg/m )

19 ± 2.94

14.32

24.61

CAT (points)

21.5 ± 3.2

16

25

278.7 ± 78.37

128

350

3.2 ± 1.8

1

4

Indexes

Duration of disease (years)
2

SMWD (meters)
Number of exacerbations per year (times)

The studied patients had high means of CAT and mMRC, short SMWD (278.7 ±
78.37 meters) and high number of exacerbation per year (3.2 ± 1.8 times). These
characteristics were similar to other studies about stem cells for COPD patients by
Weiss D.J et al (2013), Ribeiro-Paes J.T et al (2011)... [8, 9]. This is the group of
severe patients, with many clinical symptoms and poor response with basic internal
treatment. However, these studied patients had lower average of BMI when comparing
with ones in other studies. These characteristics could affect the result of stem cells later.
Table 2: Para-clinical characteristics of studied patients before treatment.
Value

X ± SD

Min

Max

WBC (G/l)

8.87 ± 2.19

6.2

12.56

CRP (mg/dL)

9.1 ± 10.14

0.9

32.9

FVC (% predicted)

65.51 ± 13.5

41.64

87

FEV1 (% predicted)

37.88 ± 13.14

16.46

64

PaO2 (mmHg)

76 ± 16.35

49

100

PaCO2 (mmHg)

47.1 ± 7.36

37

65

Indexes
Blood test:

Spirometer:

Arterial blood gases test:

The studied patients had low average
of FVC and FEV1, corresponding with
65.51 ± 13.5% predicted and 37.88 ±
162

13.14% predicted. About the results of
arterial blood gases test, mean of PaO2
was low (76 ± 16.35 mmHg), while mean


Journal of military pharmaco-medicine no8-2019
of PaCO2 was high (47.1 ± 7.36 mmHg).

These characteristics were suitable with
patient selection criteria for treatment of
stem cells. The studied patients in the
research by Weiss D.J et al (2013) had
moderate or severe obstructive degree
[8]. The study by Ribeiro-Paes J.T et al
(2011) was also carried out to treat
severe COPD patients by stem cells [9].
The studied patients had WBC at the
normal limitation. However, mean of CRP

increased (9.1 ± 10.14 mg/dL). These
characteristics were similar to the study
by Weiss D.J et al (2013), with the
mean of CRP of studied patients being
7.55 mg/dL [8]. Increased CRP showed
the status of inflammation and infection.
By treatment of stem cells, it could
reduce inflammation and inhibit infection.
Therefore, CRP is also an index to assess
the efficacy of stem cell therapy for COPD
patients.

2. Results of treatment by stem cell and PTL.
Table 3: Changes of CAT, SMWD and mMRC after treatment.
Changes
Indexes
CAT (points)

SMWD (meters)

mMRC (points)

Before
treatment (1)

After 3 months

After 6 months

p

(2)

(3)

22
(16 - 25)

21
(14 - 24)

20
(12 - 24)

p3,1 < 0.05

297,5

302,5

317,5

p2,1 > 0.05

(128 - 350)

(155 - 360)

(160 - 365)

p3,1 > 0.05

3
(3 - 3)

2,5
(2 - 3)

2,5
(2 - 3)

p2,1 < 0.05

p2,1 > 0.05

p3,1 < 0.05

The results showed that SMWD changed insignificantly. CAT and mMRC improved
clearly after 6 months, with p < 0.05. These results were similar to other previous

published studies about stem cells. The study by Ribeiro-Paes J.T et al (2011)
witnessed the COPD patients of stage 4 improved significantly their quality of life as
well as more stable clinical status [9]. Patients in the study by Stolk J et al (2016) also
had the improvement of clinical symptoms [10].
Table 4: Changes of FVC, FEV1 and PEF after treatment.
Changes
Indexes
FVC (% predicted)

FEV1 (% predicted)

PEF (% predicted)

Before
treatment (1)

After 3 months
(2)

After 6 months
(3)

p

64.5

54.2

60.7

p2,1 > 0.05

(41.6 - 87)

(38.6 - 89.5)

(34.6 - 90.8)

p3,1 > 0.05

34.5

31.14

29.45

p2,1 > 0.05

(16.46 - 64)

(16.88 - 47.88)

(14.5 - 64.3)

p3,1 > 0.05

30.5

29.05

31.1

p2,1 > 0.05

(21 - 55)

(15.8 - 44.1)

(20.2 - 57.7)

p3,1 > 0.05

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Journal of military pharmaco-medicine no8-2019
The studied patients witnessed no
improvement in spirometer indexes.
Changes of FVC, FEV1 and PEF were not
statistical (p > 0.05). PaO 2 increased
clearly after 6 months (p < 0.05), while
PaCO2 decreased lightly (p > 0.05). SaO2
changed insignificantly after treatment
(p > 0.05). These results were similar to
other previous studies about stem cells.
After treatment, COPD patients witnessed
minimal improvement of spirometer

indexes. The study by Weiss D.J et al
(2013) had the conclusion that there was

no statistical difference of spirometer
indexes when comparing the studied
group with the control one. The results
showed that there was no benefit in
improvement of respiratory function when
treated by stem cells [8]. In the study
by Ribeiro-Paes J.T et al (2011), the
respiratory indexes had a trend to decline
after 30 to 90 days [9].

Table 5: Changes of WBC and CRP after treatment.
Changes

Before
treatment (1)

After 3 months
(2)

After 6 months
(3)

p

WBC (G/l)

8.21
(6.2 - 12.56)

7.35

(5.56 - 10.83)

9.38
(5.9 - 14)

p2,1 > 0.05
p3,1 > 0.05

Neutrophil (%)

66.59
(57.3 - 92.5)

56.74
(48.8 - 69.4)

63.8
(46.81 - 75.32)

p2,1 < 0.05
p3,1 < 0.05

Lymphocyte (%)

16.21
(6.1 - 30.9)

27.85
(17.18 - 34.5)

22.66
(15.99 - 40.32)

p2,1 < 0.05
p3,1 < 0.05

CRP (mg/dl)

5.12
(0.9 - 32.9)

2.26
(0.6 - 18)

2,68
(0.92 - 17.21)

p2,1 < 0.05
p3,1 < 0.05

Indexes

The studied results showed that CRP reduced statistically at both times of 3 and
6 months after treatment (p < 0.05). The proportion of neutrophil had a trend to go
down and lymphocyte go up. WBC changed insignificantly. The characteristics of
reduced CRP were also witnessed in the studies of stem cells, carried out in
experimental animals as well as COPD patients. The COPD patients in the trial about
stem cells by Weiss D.J et al (2013) reduced CRP after 1 month. The trend of reduced
CRP was witnessed continuously during the time of trial [8].

Chart 1: Changes of arterial blood gases indexes after treatment.
PaO2 increased clearly after 6 months (p < 0.05) while PaCO2 decreased lightly
(p > 0.05). SaO2 changed insignificantly after treatment (p > 0.05).
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Journal of military pharmaco-medicine no8-2019
3. Complications of treatment by
stem cell and PLT.

hô hấp ký ở bệnh nhân BPTNMT. Tạp chí
Y học TP. Hồ Chí Minh. 2008, 12 (1), tr.96-99.

20% of patients had fever after treatment
of MSCs and 1 patient witnessed a
moderate exacerbation. There was no
anaphylaxis, dead or new tumor formation.
These results were similar to other previous
studies about stem cells. The patients in
the study by Ribeiro-Paes J.T et al (2011)
were followed up within 1 year after
treatment. There was no complication [9].
The trial by Weiss et al (2013) also showed
that there was no statistical clinical
adverse event during the follow-up time
after treatment [8]. These adverse events
were mild and there was no correlation
found between these ones and treatment
of stem cells. This result proved that
treatment of stem cells is a safe method.

3. Global Intiative for Chronic Obstructive
Lung Disease. Global strategy for diagnosis,
management and prevention of chronic
obstructive pulmonary disease. https://goldcopd.
org/gold-2017-global-strategy-diagnosismanagement-prevention-copd.2018.

CONCLUSSIONS
Studying the initial results of MSCs in
combination with PLT in 10 COPD patients,
we had some following conclusions:
- CAT and mMRC improved clearly after
6 months. There was no improvement
in spirometer indexes. CRP reduced
statistically (p < 0.05). PaO2 increased
clearly after 6 months (p < 0.05) while
PaCO2 decreased lightly (p > 0.05).
- Treatment by stem cells is safe: 20%
of patients had fever and 1 patient had a
moderate exacerbation. There was no
anaphylaxis, dead or new tumor formation.
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