Stem Cell Research - Assignment Essays

Research Process

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Findings from Netherlands Cancer Institute in Breast Cancer
Reported (High-dose chemotherapy with stem cell rescue to
treat stage III homologous deficient breast cancer: factors
influencing clinical implementation).
Date: Jan. 26, 2023
From: Women’s Health Weekly
Publisher: NewsRX LLC
Document Type: Article
Length: 495 words

Full Text:
2023 JAN 26 (NewsRx) — By a News Reporter-Staff News Editor at Women’s Health Weekly — Researchers detail new data in breast
cancer. According to news originating from the Netherlands Cancer Institute by NewsRx correspondents, research stated, “High-dose
chemotherapy with autologous stem cell rescue (HDCT) is a promising treatment for patients with stage III, HER2-negative,
homologous recombination deficient (HRD) breast cancer. Clinical effectiveness and cost-effectiveness are currently under
investigation in an international multicenter randomized controlled trial.”

Financial supporters for this research include Kwf Kankerbestrijding; Zonmw.

Our news reporters obtained a quote from the research from Netherlands Cancer Institute: “To increase the chance of successful
introduction of HDCT into daily clinical practice, we aimed to identify relevant factors for smooth implementation using an early
comprehensive assessment framework. This is a qualitative, multi-stakeholder, exploratory research using semi-structured interviews
guided by the Constructive Technology Assessment model, which evaluates the quality of a novel health technology by clinical,
economic, patient-related, and organizational factors. Stakeholders were recruited by purposeful stratified sampling and interviewed
until sufficient content saturation was reached. Two researchers independently created themes, categories, and subcategories by
following inductive coding steps, these were verified by a third researcher. We interviewed 28 stakeholders between June 2019 and
April 2021. In total, five overarching themes and seventeen categories were identified. Important findings for optimal implementation
included the structural identification and referral of all eligible patients, early integration of supportive care, multidisciplinary
collaboration between- and within hospitals, (de)centralization of treatment aspects, the provision of information for patients and
healthcare professionals, and compliance to new regulation for the BRCA1-like test.”

According to the news editors, the research concluded: “In anticipation of a positive reimbursement decision, we recommend to take
the highlighted implementation factors into consideration. This might expedite and guide high-quality equitable access to HDCT for
patients with stage III, HER2-negative, HRD breast cancer in the Netherlands.”

For more information on this research see: High-dose chemotherapy with stem cell rescue to treat stage III homologous deficient
breast cancer: factors influencing clinical implementation. BMC Cancer, 2023,23(1):1-11. (BMC Cancer –
http://bmccancer.biomedcentral.com). The publisher for BMC Cancer is BMC.

A free version of this journal article is available at https://doi.org/10.1186/s12885-022-10412-x.

Our news journalists report that more information may be obtained by contacting Joost G. E. Verbeek, Division of Psychosocial
Research and Epidemiology, Netherlands Cancer Institute. Additional authors for this research include Vincent M. T. de Jong, Hanna
M. Wijnja, Agnes Jager, Sabine C. Linn, Valesca P. Retel, Wim H. van Harten.

Keywords for this news article include: Netherlands Cancer Institute, Oncology, Technology, Chemotherapy, Breast Cancer,
Women’s Health, Stem Cell Research, Drugs and Therapies, Health and Medicine.

The citation for this news report is: NewsRx. Findings from Netherlands Cancer Institute in Breast Cancer Reported (High-dose
chemotherapy with stem cell rescue to treat stage III homologous deficient breast cancer: factors influencing clinical implementation).
Women’s Health Weekly. January 26, 2023; p 2024.

Copyright: COPYRIGHT 2023 NewsRX LLC
http://www.newsrx.com/newsletters/Womens-Health-Weekly.html
Source Citation (MLA 9th Edition)
“Findings from Netherlands Cancer Institute in Breast Cancer Reported (High-dose chemotherapy with stem cell rescue to treat stage

III homologous deficient breast cancer: factors influencing clinical implementation).” Women’s Health Weekly, 26 Jan. 2023, p.
2024. Gale OneFile: Business, link.gale.com/apps/doc/A734154513/GPS?u=lirn50909&sid=bookmark-GPS&xid=36a3295f.
Accessed 7 Feb. 2023.

Gale Document Number: GALE|A734154513

http://www.newsrx.com/newsletters/Womens-Health-Weekly.html

Findings from Taipei Tzu Chi Hospital Advance Knowledge in
Breast Cancer (Breast Cancer with Increased Drug
Resistance, Invasion Ability, and Cancer Stem Cell Properties
through Metabolism Reprogramming).
Date: Dec. 1, 2022
From: Women’s Health Weekly
Publisher: NewsRX LLC
Document Type: Article
Length: 537 words

Full Text:
2022 DEC 1 (NewsRx) — By a News Reporter-Staff News Editor at Women’s Health Weekly — A new study on breast cancer is now
available. According to news reporting originating from the Taipei Tzu Chi Hospital by NewsRx correspondents, research stated,
“Breast cancer is a heterogeneous disease, and the survival rate of patients with breast cancer strongly depends on their stage and
clinicopathological features. Chemoradiation therapy is commonly employed to improve the survivability of patients with advanced
breast cancer.”

Funders for this research include Ministry of Science Technology; Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation.

The news editors obtained a quote from the research from Taipei Tzu Chi Hospital: “However, the treatment process is often
accompanied by the development of drug resistance, which eventually leads to treatment failure. Metabolism reprogramming has
been recognized as a mechanism of breast cancer resistance. In this study, we established a doxorubicin-resistant MCF-7 (MCF-7-
D500) cell line through a series of long-term doxorubicin in vitro treatments. Our data revealed that MCF-7-D500 cells exhibited
increased multiple-drug resistance, cancer stemness, and invasiveness compared with parental cells. We analyzed the metabolic
profiles of MCF-7 and MCF-7-D500 cells through liquid chromatography-mass spectrometry. We observed significant changes in 25
metabolites, of which, 21 exhibited increased levels (>1.5-fold change and * * p* * < 0.05) and 4 exhibited decreased levels (<0.75- fold change and * * p* * < 0.05) in MCF-7 cells with doxorubicin resistance. These results suggest the involvement of metabolism reprogramming in the development of drug resistance in breast cancer, especially the activation of glycolysis, the tricarboxylic acid (TCA) cycle, and the hexamine biosynthesis pathway (HBP)."

According to the news editors, the research concluded: “Furthermore, most of the enzymes involved in glycolysis, the HBP, and the
TCA cycle were upregulated in MCF-7-D500 cells and contributed to the poor prognosis of patients with breast cancer. Our findings
provide new insights into the regulation of drug resistance in breast cancer, and these drug resistance-related metabolic pathways
can serve as targets for the treatment of chemoresistance in breast cancer.”

For more information on this research see: Breast Cancer with Increased Drug Resistance, Invasion Ability, and Cancer Stem Cell
Properties through Metabolism Reprogramming. International Journal of Molecular Sciences, 2022,23(12875):12875. (International
Journal of Molecular Sciences – http://www.mdpi.com/journal/ijms). The publisher for International Journal of Molecular Sciences is
MDPI AG.

A free version of this journal article is available at https://doi.org/10.3390/ijms232112875.

Our news journalists report that additional information may be obtained by contacting Kian-Hwee Chong, Department of Surgery,
Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 23142, Taiwan. Additional authors for this research
include Yao-Jen Chang, Wei-Hsin Hsu, Ya-Ting Tu, Yi-Ru Chen, Ming-Cheng Lee, Kuo-Wang Tsai.

Keywords for this news article include: Taipei Tzu Chi Hospital, Antibiotics, Antineoplastics, Pharmaceuticals, Oncology, Breast
Cancer, Women’s Health, Drug Resistance, Stem Cell Research, Doxorubicin Therapy, Drugs and Therapies, Health and Medicine.

The citation for this news report is: NewsRx. Findings from Taipei Tzu Chi Hospital Advance Knowledge in Breast Cancer (Breast
Cancer with Increased Drug Resistance, Invasion Ability, and Cancer Stem Cell Properties through Metabolism Reprogramming).
Women’s Health Weekly. December 1, 2022; p 211.

Copyright: COPYRIGHT 2022 NewsRX LLC
http://www.newsrx.com/newsletters/Womens-Health-Weekly.html
Source Citation (MLA 9th Edition)
“Findings from Taipei Tzu Chi Hospital Advance Knowledge in Breast Cancer (Breast Cancer with Increased Drug Resistance,

Invasion Ability, and Cancer Stem Cell Properties through Metabolism Reprogramming).” Women’s Health Weekly, 1 Dec. 2022,
p. 211. Gale OneFile: Business, link.gale.com/apps/doc/A728037888/GPS?u=lirn50909&sid=bookmark-GPS&xid=ee0d9497.
Accessed 7 Feb. 2023.

Gale Document Number: GALE|A728037888

http://www.newsrx.com/newsletters/Womens-Health-Weekly.html

Asian Journal of Nursing Education and Research. 10(4): October- December, 2020

521

ISSN 2231-1149 (Print)

2349-2996 (Online)
DOI: 10.5958/2349-2996.2020.00113.5

Vol. 10 |Issue-04|

October – December| 2020

Available online at

www.anvpublication.org

Asian Journal of

Nursing Education and Research
Home page www.ajner.com

RESEARCH ARTICLE

Acute Graft versus Host Disease Post Allogeneic Stem Cell

Transplantation- A case report

Mrs. Abijah Princy B.1*, Mrs. Amalorpavamari Lucas2, Mrs. Jayakumari J.3
1Reader, College of Nursing, Christian Medical College, Vellore – 632 004,

Tamil Nadu India.

2Professor, College of Nursing, Acting HOD, Hemato – Oncology Nursing, Christian Medical College,

Vellore – 632 004, Tamil Nadu India.
3Charge Nurse, Bone Marrow Transplant Unit, Christian Medical College, Vellore – 632 004,

Tamil Nadu India.

*Corresponding Author Email: abijahprincyb@gmail.com

ABSTRACT:
Allogeneic Stem cell transplantation remains the standard of care in many of the hematological disorders and

genetic disorders. Despite advances in prevention and management of acute Graft versus Host Disease(aGvHD),

it continues to be a major challenge and most common immunogenic complication post Allogeneic stem cell

transplantation accounting for early transplant related morbidity and non relapse mortality. aGvHD is an immune

triggered process, causing profound immune dysregulation and organ dysfunction. GvHD occurs when immune

cells transplanted from a non-identical donor (graft) into the recipient (host) recognize the host cells as ‘foreign’,

thereby initiating a graft-versus-host reaction. It considerably influences the overall success rate of allogeneic

stem cell transplantation imposing a major impact in the quality of life among transplant survivors. Therefore, it

is crucial to understand the pathophysiology, clinical presentation and management of this acute complication in

order to improve clinical outcomes and to foster wholistic nursing care for patients undergoing allogeneic stem

cell transplantation.

KEYWORDS: aGvHD, Allogeneic stem cell transplantation

INTRODUCTION:
The only curative therapy for many of the hematological

disorders as well as immune deficiency disorders, inborn

errors of metabolism, genetic disorders and some of the

solid tumors is allogeneic stem cell transplantation.

Despite advances in HLA typing, GvHD intensive

prophylaxis and post transplant immunosuppressive

therapy, GvHD remains a major complication of concern

attributing to transplant related mortality.

Received on 29.06.2020 Modified on 08.08.2020

Asian J. Nursing Education and Research. 2020; 10(4):521-528.
DOI: 10.5958/2349-2996.2020.00113.5

aGvHD occurs when the transplanted donor T

lymphocytes recognize antigenic disparities between the

host and recipient. Inflammatory cytokine release has

been implicated as the primary mediator of aGvHD and

activation of T cells is one step in the complex process.

Deregulated cytokine release by cells other than T cells

leads to tissue damage associated with aGvHD.1 aGvHD

predisposes to multi-organ syndromes of tissue

inflammation and or fibrosis that primarily affect skin,

gastrointestinal tract, liver and mucosal surfaces.

Clinically, GvHD is described as acute GvHD when it

occurs within 100 days after Hematopoietic Stem Cell

Transplantation (HSCT) or chronic GvHD which occurs

after 100 days, but these syndromes may overlap in time.

Asian Journal of Nursing Education and Research. 10(4): October- December, 2020

522

Epidemiology:

Acute GvHD is the second leading cause of death, after

disease relapse following allogeneic HSCT.2 The exact

incidence of aGvHD after allogeneic HSCT is unknown.

Reported incidence rates range from 9 to 50% in patients

who undergo allogeneic HSCT from a genotypically

HLA identical sibling. Acute GvHD is also common in

matched unrelated donors and in haplo identical related

donors.3 With matched related and unrelated donors, the

cumulative incidence of acute GvHD remains

approximately 40-60% respectively.4 It has been

estimated that 20-50% of all transplanted patients

experience grade 2 or more aGvHD despite immuno-

suppressive prophylaxis.1

Risk factors:

The risk factors of aGvHD are multifactorial and have

been studied intensively over the last three decades.

These include:

• Human leukocyte antigen (HLA) disparity

• Increased age in donor and recipient

• Multiparous female donor

• Donor and recipient sex mismatch

• Increased dose of total-body irradiation(TBI)

• Full intensity conditioning regimen

• Ineffective acute GvHD prophylaxis

• Source of the graft/unrelated donor

• Lack of protective environments

• Splenectomy

• Immunoglobulin use

• Pre transplant comorbidities

• ABO compatibility

• Prior exposure to Herpes viruses

• Donor transfusions

• Performance score

• Antibiotic gut decontamination

• Post-transplant transfusion

Further, acute GvHD also differs by disease, Acute

leukemia compared with other hematologic malignancies

is a significant risk factor for aGvHD.5,3 Certain cellular

markers in donor grafts, most notably, the T cell subsets

expressing IL-7 receptor-α (CD127) and PD-1 and

elevated levels of tumor necrosis factor-α in both graft

and patient before HSCT posed risk of aGvHD

development.6 Transplantation with an identical sibling

donor and the use of ATG in the conditioning regimen

containing TBI have been associated with a decreased

risk of grades II–IV aGvHD.7

Classification:

GvHD is sub classified based on the timing of

presentation and the features present as follows:

• Classic acute GvHD: Cases present within 100 days

of HSCT and display features of aGvHD. Diagnostic

and distinctive features of chronic GVHD are absent.

• Persistent, recurrent, late onset acute GvHD:

Cases present greater than 100 days post-HSCT with

features of aGvHD. Diagnostic and distinctive

features of chronic GvHD are absent

• Classic chronic GvHD: Cases may present at any

time post-HCT. Diagnostic and distinctive features of

chronic GvHD are present. There are no features of

acute GvHD.

• Overlap syndrome: Cases may present at any time

post-HSCT with features of both chronic GvHD and

acute GvHD. On occasion, this is colloquially

referred to as “acute on chronic” GvHD.8

Pathophysiology:

GvHD occurs as the donor cells are not identical with the

recipient (patient) cells. This leads to a fight between the

T cells of the donor and the host immune system.

Development aGvHD involves 3 phases as shown below

(Fig 1). Donor T lymphocytes play the crucial role of

mediating GvHD following interactions with activated

host and donor antigen-presenting cells (APC). A

complex network of cytokines, chemokines, cellular

receptors and immune cell subsets then modulate T-

cell/APC interactions that result in GvHD.9 The

inflammatory cascade and continued tissue damage can

lead to release of biomarkers of aGvHD into the

circulation even before the onset of clinical signs of

GvHD potentially predicting therapy responses. These

biomarkers include soluble CD30 from activated T cells,

elafin (skin-specific), regenerating islet-derived 3-α

(REG3α;gut-specific), suppressor of tumorigenicity 2

(ST2; a member of the IL-1 receptor family–binding IL-

33), microRNA and others.10 As counterparts to the

effector cells, the T regulatory cells (T reg) suppress

GvHD and also impairs the target tissue homing of

effector cells.1

Asian Journal of Nursing Education and Research. 10(4): October- December, 2020

523

Fig 1: Three phase development of aGvHD1

Staging and Grading:

Acute GvHD is clinically graded and staged in severity from grades I to IV depending on the extent of skin, liver

and gut involvement.

Table 1: Sages of aGvHD2

Clinical

stage

Lower GI Upper GI Liver

(Bilirubin level in mg/dl)

Skin

(% rash of body surface area)

1. Diarrhea <500 ml/day Nausea/vomiting 2-3 <25%

2. Diarrhea 500-1000 ml/day 3-6 25-50%

3. Diarrhea 1000-1500 ml/day 6-15 >50% Generalized erythroderma

4. Diarrhea >1500ml/day >15 Bullae/ desquamation

Table 2: Grading of aGvHD2

Overall clinical

grade

Lower GI Upper GI Liver Skin

I 0 0 0 1-2

II 1 1 1 3

III 2-3 2-4 –

IV 4 – 4

Clinical manifestations:

Clinical manifestations of aGvHD include specific

derangements in the skin, liver and gastrointestinal tract,

occasionally the eyes and oral mucosa. It often presents

with skin rash, diarrhea, elevated bilirubin, and it is

associated with recurrent infections.

Acute Skin GvHD:

Characterised by maculopapular rash, sometimes pruritic

or painful. Typically distributed on the palm of the hands

and soles of the feet, later progresses to the face, neck,

upper chest and trunk. Stage III shows generalized

erythroderma with bullae formation and desquamation of

the epidermal layers of the skin.

Acute liver GvHD:

Characterized by an isolated hyperbilirubinemia. The

increase in alkaline phosphatase is seen more frequently

than liver enzyme abnormalities.

Acute Gastrointestinal GvHD:

Exhibit profuse diarrhea with anorexia and sometimes

nausea. Progression with abdominal pain, GI bleeding

and ileus is associated with later stages of GvHD1

The most common target organ of aGvHD is the skin,

followed by the gastrointestinal tract.7 The mortality risk

varies depending on the stage and grade of aGvHD2

Diagnosis:

Diagnosis of aGvHD can be made as follows:

• Clinically in patients presenting with a rash, diarrhea

and elevation of bilirubin within the first several

weeks of transplant.

• Skin and liver biopsies

• Plasma biomarkers: IL-2-receptor-a, TNF receptor-1,

IL-8 and hepatocyte growth factor has been

suggested as a confirmatory tool for the diagnosis of

aGvHD at the onset of clinical symptoms and to

Asian Journal of Nursing Education and Research. 10(4): October- December, 2020

524

provide prognostic information independent of

GvHD severity.2

Management:

Treatment should be tailored based on the severity of

presentation and symptom management. Calcineurin

inhibitors are the cornerstone of prophylaxis, while

steroids remain the gold standard of treatment.4

• Methyl Prednisolone (Systemic corticosteroid) is

given at 2mg/kg/day given in 2 divided doses in

grade III-IV, while 0.5 to 1mg/kg/day for grade II

disease.

• The original immune suppressive prophylaxis must

be continued. Median time to resolution of aGvHD is

30-42 days.

• In patients who respond to initial therapy, short-term

tapering treatment with prednisone to a cumulative

dose of 2,000mg/m2 is effective and expected to

minimize steroid-related

complications.

• In steroid refractory cases, alternative therapies

include antithymocyte globulin (ATG), cyclosporine,

mycophenolate mofetil, anti-IL-2 receptor, anti-CD5-

specific immunotoxin, pan T-cell ricin A-chain

immunotoxin, ABX-CBL, etarnercept, infliximab,

daclizumab, vilizumab and pentostatin. These agents

can be used alone or in combination.

• The use of mesenchymal stem cell in steroid-

refractory aGvHD is found to be useful for patients

with lower grade aGvHD with only skin

involvement. Extracorporeal photopheresis also

shows promise as a less immunosuppressive strategy

to reduce rates of aGvHD.2

Prevention:

Prevention of aGvHD is the most vital dimension in

patients undergoing allogeneic HSCT. Prophylaxis is

mainly based on immunosuppression achieved either by

T cell depletion or pharmacologically. The most

commonly used GvHD prophylaxis following full

intensity conditioning regimen includes a Calceneurin

Inhibitor (e.g. Cyclosporine, Tacrolimus) with

Methotrexate or MMF. Recently, Sirolimus which is a

commonly used immunosuppressant in solid organ

transplantation is also used for GvHD prophylaxis.2

Several studies support that combination of sirolimus

and tacrolimus promoted rapid engraftment, lowered

acute GvHD incidence, reduced transplant-related

toxicity and improved survival.11

Prognosis:

The overall survival at one year is about 20-30%.

Corticosteroid-refractory aGvHD has a poor prognosis

and the second-line therapies have high failure rates.12

• Patients with moderate to severe GvHD have a

significantly higher mortality rate compared with

those with mild disease. Estimated five-year survival

rates of patients with grade III (C) and grade IV (D)

acute GvHD are 25 and 5 percent, respectively.

• Patients with the same grade but different patterns of

skin, gut or liver involvement often have

significantly different outcomes. As an example, a

patient with stage IV cutaneous GvHD alone would

be expected to have a much more favorable outcome

than a patient with stage IV gastrointestinal GvHD

alone, although both have overall grade IV GvHD.13

Nursing Management of a patient with Acute GVHD:

Nursing management in Acute GvHD is discussed using

a case report and nursing process approach

Case Report:

Baby A., a 4 year old is the only daughter of an affluent

non consanguineous parents in Uganda. She was

evaluated in her home town for fever at 1 year of age and

was diagnosed to have Sickle cell Anemia. She also

developed recurrent painful bony crisis and severe back

ache for 3 years with several episodes of upper

respiratory tract infection within 3 months for which she

was repeatedly treated with antibiotics and blood

transfusion. In view of these complaints Baby A. was

referred to a tertiary care hospital in India for definitive

management. On examination, child looked pale, had

hepatomegaly of 2 cm below the right costal margin.

Had no icterus, cyanosis, clubbing, peripheral

lymphadenopathy or splenomegaly. Her mutation

analysis confirmed Homozygous Sickle cell Anemia,

Hemoglobin was 8.9g%, Liver function tests were

elevated (Blirubin-2.47mg/dl, SGOT-62U/L), Serum

Ferritin was 439ng. Ultrasonography of abdomen

revealed small ringed spleen. MRI brain suggested subtle

focal changes of right terminal Internal Carotid artery.

Cardiac, dental and ENT clearance was obtained as part

of transplant work up. Due to unavailability of sibling

donor and matched unrelated donor, Baby A. underwent

Haplo-identical Allogeneic Stem Cell Transplantation

with her mother being the donor (32 years).

HLA typing:
HLA: 5/10 A locus B Locus C Locus DR Locus

DRBI

DQ Locus

DQB1

Baby A.

PATIENT

36:01

68:02:01G

15:10:01

58:01:01G

03:04:02

03:02:01G

03:01:01G

07:01:01G

02:01:01G

Mrs. M

DONOR

02:01:01G

36:01

15:10:01

42:01:01

03:04:02

17:01:01G

03:02:01

03:01:01G

02:01:01G

04:02:01G

Asian Journal of Nursing Education and Research. 10(4): October- December, 2020

525

Conditioning regimen protocol: she received the

following condition regimen and tolerated them without

any complications:

• Inj. Thiotepa 8mg/kg on day -6 (155mg)

• Inj. Treosulfan 14gm/m2/day on day -5, -4 (10gm) to

day -3 (13gm)

• Inj. Fludarabine 40mg/m2/day from day -5, -4, -3 (30

mg) to day-2 (33mg)

• Inj. Rituximab 375mg/m2 (300mg) on day-1

• Total Body Irradiation (200cGy) on day -1

After alpha beta T cell depletion, 190ml of Stem cell

product with CD 34 cell dose of 10.2 x106 cells/Kg was

infused. No immediate complication was noted during

the infusion. She achieved complete chimerism status on

Day 28. Post HSCT, she developed Febrile Neutropenia

from day +12 and multiple infections (Day+33:

Enterococcus faecium and Klebsiella Pneumonia CRO

Sepsis). She received Inj. Amikacin 340mg od, Inj.

Meropenem 750mg Q8h, Inj. Colistin 2.5 MU Q8h, Inj.

Teicoplanin 200mg Q12h, Inj. Metronidazole 150mg and

was on Ionotropic support. For fungal pneumonia she

was managed with Inj. Amphotericin B 50mg od and

Inj.Caspofungin 35mg bd. On day +4, she developed

Grade II mucositis which was managed with Total

Parenteral Nutrition and opioid analgesics infusion.

Mucositis improved as the Neutrophil Engraftment

occurred. Child also developed BK virus and Adeno

virus infection inspite of the prophylaxis with Tab.

Leflunamide 100mg and Inj. Ciprofloxacin 100mg bd.

Hence, she received Inj. Cidofovir 75mg (once a week).

She developed severe painful oral ulcers on day +48 due

to Herpes simplex virus 1 and was given Inj. Acyclovir

10mg/kg for 16 days.

In addition to the T cell depleted stem cell infusion, Inj.

Cyclosporine 480mg bd was given additionally to

prevent GvHD. Child started showing symptoms of

acute Gastro intestinal GvHD since day +12 with

progressively worsening symptoms from grade II to

grade IV disease presenting with diarrhoea, abdominal

distention, pain, paralytic ileus, and hematochezia. She

was initially managed with Inj. Methyl prednisalone

18mg IV and Inj. Octreotide 100mcg od. On day +41

and day +65, she received 2 doses of CD 45 RO cells

(3.7 x106 cell/kg) reinfusion from the cryopreserved

donor samples. She also received IVIG 400mg/kg (10g)

on day +7, +24, +29. Inj. Cyclosporine was stopped as

she developed symptoms of cyclosporine induced

Posterior Reversible Encephalopathy Syndrome (PRES).

She was on low dose of Tacrolimus 0.25mg bd. Inj.

Methyl prednisalone was tapered and stopped as she

developed steroid refractory Gastro intestinal GvHD. Inj.

Ruxolinitib 5mg was given od, Inj. Basiluximab 20mg

IV was given once a week. She was on nil per oral

status

on Total Parenteral Nutritional support. On day +100,

she was able tolerate feeds. She got discharged from the

hospital on day +191 during which, she was

asymptomatic, ambulant and on oral diet. She is

followed up in out-patient basis once in 3 months and

subsequently every 6 months. Her day +60 and day +90

chimerism status was complete.

NURSING CARE:
1. Nursing diagnosis:

Actual infection related to immunosuppression

secondary to myeloablative chemotherapy, total body

irradiation, Probable fungal pneumonia, Enterococcus

faecium sepsis, Klebsiella pneumonia CRO sepsis, adeno

virus, BK virus positive status

Expected outcome: Infection is minimised as evidenced

by normothermia, negative blood surveillance culture,

normal chest radiograph, ANC >1500mm3

Nursing interventions

• Inspected for signs of infection including fever,

chills, vomiting, diarrhea, cough. WBC mm3.

Developed fever of 1010 F on day +1 which was

managed with Managed with Inj. Meropenem and

Inj. Amikacin.

• Developed high grade fever, flushing and diarrhoea

on day +11, +16 with signs of septic shock. On day

+33, developed a breakthrough high grade fever,

High resolution CT revealed left lobe superior

segment consolidation. Day +50, blood culture

revealed Enterococcus faecium sensitive to

Teicoplanin, Carbopenemase resistant Klebsiella

pneumonia sensitive to Colistin and Teigicyclin. Inj.

Teicoplanin, Inj. Colistin and Inj. Caspofungin, Inj.

Metronidazole, Inj. Liposomal Amphotericin B,

Ionotropic support

• Monitored the central venous access device site for

infection and performed weekly dressing

meticulously. Hickmann’s catheter was removed on

day +56

• Obtained chest X ray, cultures and sensitivities,

• Regularly monitored (twice a week) for Blood CMV

and urine BK virus reactivation. Started on Tab.

Leflunamide and Inj. Ciprofloxacin (CMV and BK

virus prophylaxis)

• Day +33 developed asymptomatic BK viruria with

quantitative viral load of 10.33 log. Received Inj.

Cidofovir 75mg (once a week). On Day +41

adenovirus PCR became positive. Day +75,

developed high viral load (Log 7.31), restarted Inj.

Cidofovir (4 doses). Developed several painful oral

ulcers at the tongue, floor of mouth and palate. Day

+48: Tissue scraping from oral ulcers revealed HSV

1 Viral PCR was positive (Inj. Acyclovir10mg/kg for

16 days)

• Adopted reverse barrier nursing technique (protective

isolation)

Asian Journal of Nursing Education and Research. 10(4): October- December, 2020

526

• Ensured vigorous hand washing. Maintained aseptic

technique while performing procedures. Taught on

prevention of infection

• Practiced meticulous oral/ body hygiene

• Instituted low microbial diet with high calories,

proteins, vitamin C, minerals and

fluids

• Administered antimicrobial therapy:

Evaluation:

Infection was minimised. Patient had negative blood

culture report. Afebrile. Had clear lung sounds. WBC-

6100/cumm. Day +43, BK virus load became negative.

Tzanck smear was negative.

2. Nursing diagnosis:

Ineffective protection related to Myelosuppression

secondary to chemotherapy/total body irradiation, Gastro

intestinal GvHD, post transplant immunosuppressive

therapy, drug injury (prolonged antimicrobial therapy),

nutritional deficiencies.

Expected outcome:

Patient achieves optimal body functioning as evidenced

by improvement in Gastro intestinal GvHD, general

health status and absence of treatment related

complications.

Nursing interventions:

• Monitored vital signs

• Assessed for post stem cell transplant complications:

• Observed for signs and symptoms of pancytopenia/

myelosuppression. Monitored complete blood counts.

• Administered blood products(Irradiated packed red

cells:20, Irradiated platelet rich concentrates:6, fresh

frozen plasma:7) and granulocyte colony stimulating

factor 50mcg 3/7.

• Monitored for side effects of chemotherapy,

radiation, antimicrobial therapy such as nausea,

vomiting, bone marrow suppression, diarrhoea,

alopecia and infection.

• Assisted in rectal biopsy. Administered steroids and

immunosuppressants.

On day +11 administered Inj. Cyclosporine in addition to

alpha beta T cell depletion of stem cells. On day +12 she

developed Diarrhoea, Rectal biopsy showed Gastro

intestinal GvHD grade 1. Was started on Inj. Methyl

Prednisalone 18mg IV od (+13) to bd (+15). Diarrhea

worsened on day+17(Grade III GvHD). Started on Inj.

Cyclophosphamide 475mg (25mg/kg), Inj. Etanercept

7mg S/C od twice a week, Oral Budesonide

• Assessed the nutritional status. Kept her on nil per

oral status. NG tube to dependent drainage. Provided

parenteral nutrition

• Day +19 she developed cyclosporine induced

Posterior Reversible Encephalopathy Syndrome.

Hence Cyclosporine was stopped.

• Day +23 diarrhoea persisted Inj. Octreotide infusion

was started. Day+30 started on low dose Tacrolimus

(0.25mg bd). Tapered Methyl prednisolone as she

developed steroid refractory Grade IV GvHD.

• Day +45 she developed abdominal distention and

pain suggestive of paralytic ileus.

• Inj. Ruxolinitib (Jakafi) 5mg and Inj. Basiluximab

20mg IV once a week was given as she developed

hematochezia.

Evaluation:

There was marked improvement in GvHD. Infection was

controlled.WBC mm3 Vital signs were stable.

Chimerism was complete on day+28, +60, +90. Was

able to tolerate oral food

3. Nursing diagnosis:

Diarrhoea related to Grade IV Gastro intestinal GvHD,

side effects of conditioning regimen and antibiotic/ drug

intolerance

Expected outcome:

Diarrhoea is controlled as evidenced by patient passing

soft, formed stool not more than thrice a day

Nursing interventions:

• Checked bowel sounds, observed for abdominal

distention, rigidity and pain

• Observed the stool pattern, recorded frequency,

character and volume. Had severe abdominal pain,

loose stools and hematochezia.

• Monitored vital signs for deficient fluid volume

• Obtained stool specimen for culture and sensitivity.

Assisted for rectal biopsy to rule out Gastro intestinal

GvHD grading. Rectal biopsy revealed evidence of

grade IV Gastro intestinal GvHD

• Administered Oral Rehydration Solution after each

episode of loose stools

• Administered IV fluids. Monitored intake output

chart.

• Administered parenteral nutrition, steroids and

antibiotics for GvHD management

Evaluation:

Patient passed soft formed stool. There was complete

improvement in Gastro intestinal GvHD. On day +100

child was able to tolerate oral feeds.

4. Nursing diagnosis:

Impaired oral mucosal membrane related to side effects

of chemotherapy/ total body irradiation

Asian Journal of Nursing Education and Research. 10(4): October- December, 2020

527

Expected outcome:

She achieves optimal integrity of the oral mucosal

membrane as evidenced by absence of mucositis

Nursing interventions:

• Assessed the oral mucous membrane. Had painful

oral ulcers (Grade II oral mucositis)

• Kept on NPO status, administered Total Parenteral

Nutrition

• Administered opioid analgesics

• Encouraged mouth wash using diluted 7% Sodium

bicarbonate followed by 2% Chlorhexidine solution 4

times/day as the mucositis improved

• Encouraged GvHD diet once tolerant to oral diet

• Encouraged 2-3 litres of water/day

Evaluation:

Grade 2 oral mucositis completely resolved as the

neutrophil engraftment occurred. She was able to tolerate

normal diet.

5. Nursing diagnosis:

Imbalanced nutrition less than body requirement related

to grade IV Gastro intestinal GvHD, side effects of

conditioning regimen, malabsorption of nutrients,

increased metabolic rate secondary to fever/infection

Expected outcome:

Patient achieves optimal nutritional status and protein

stores as evidenced by adequate calorie intake based on

body requirement and weight gain

Nursing interventions:

• Determined specific causes for imbalanced nutrition.

Auscultated for bowel sounds. Assessed the

nutritional status

• Monitored lab values: Hb- 8.9g%, WBC-

6100/cumm, serum Ferritin-439 ng%, total protein-

6.9g/dl, albumin-4.3g/dl

• Evaluated the effectiveness of antiemetic and

antidiarrheal therapy

• Assessed her food preferences

• Administered parenteral nutrition and intravenous

fluids

• Implemented GvHD diet after maintaining NPO

status

• Implemented meticulous oral hygiene with 2%

chlorhexidine solution Q4 hourly

Evaluation:

Child’s nutritional status gradually improved. Parenteral

nutrition was stopped. Paralytic ileus symptoms

resolved. She was able to tolerate oral feeds from day

+100. There was significant weight gain.

6. Nursing diagnosis:

Fatigue related to decreased oxygen carrying capacity of

blood, NPO status, pain, side effects of chemotherapy/

radiation, hyperthermia, infection

Expected outcome:

Child attains optimal energy and activity tolerance as

evidenced by ability to play and perform her ADLs

Nursing interventions:

• Assessed the level of fatigue and the specific causes

of fatigue

• Assisted in planning the ADLs, prioritized the

activities with the

parents

• Encouraged frequent rest periods after activity

• Transfused blood when haemoglobin was less than

8g%. She received 20 units of Irradiated Packed red

cells during the peri transplant period

• Encouraged high protein, high calorie diet.

Administered total parenteral nutrition

• Instituted supplemental oxygen therapy(2- 4litres)

• Administered antipyretics(Inj. Febrinil 250mg prn)

and antibiotics/ antifungal and antiviral medications

Evaluation:

There was improvement in child’s energy level. She was

able to perform ADLs and play actively.

7. Nursing diagnosis:

Anxiety (Parental) related to high risk procedure,

uncertainty of treatment outcome and hospitalization

Expected outcome:

Anxiety is minimised as evidenced by adopting positive

coping mechanisms and restful appearance

Nursing interventions:

• Acknowledged awareness of the parent’s anxiety.

Examined anxiety provoking situations

• Reassured and provided a non-threatening

environment

• Oriented them to new experiences, procedures and

people in the Bone marrow transplant Unit

• Involved patient in play therapy

• Encouraged verbalization of feelings and cleared

their doubts in simple language

Evaluation:

Anxiety was minimised. Parents were restful and calm.

They verbalised familiarity over the environment and

procedure

8. Nursing diagnosis:

Knowledge deficit regarding disease process, procedures

and treatments in hematopoietic stem cell

Asian Journal of Nursing Education and Research. 10(4): October- December, 2020

528

transplantation, complications, home care and follow up

related to lack of information

Expected outcome:

Learning needs are met regarding disease process,

procedures and treatments in hematopoietic stem cell

transplantation, complications, home care and follow up

as evidenced by verbalization of understanding by

parents

Nursing interventions:

• Assessed the parent’s level of knowledge and

understanding of disease process, procedures,

treatment plan and follow up after discharge

• Explained on Sickle cell anemia, haplo-identical

allogeneic stem cell transplantation including harvest

procedure, conditioning, engraftment, side effects,

complications including GvHD and the physical set

up of bone marrow transplantation unit

• Explained the need for infection control, care of

central venous access device, antiobiotic/ antifungal/

antiviral therapy, low microbial diet, total parenteral

nutrition and blood transfusion.

• Discussed on follow up schedule and home care

Evaluation:

Parents verbalised understanding and confidence in

caring for Baby A.

CONCLUSION:
aGvHD highlights the need for appropriate risk

reduction while HSCT planning, patient tailored

prophylaxis, prompt assessment and monitoring, early

detection aid to appropriate management and expected

treatment outcome. There is a tremendous role of

hematology nurse while caring for patients with aGvHD.

CONFLICT OF INTEREST:
The authors have declared no conflicts of interest.

REFERENCE:
1. Ball LM, Egeler RM. Acute GvHD: pathogenesis and

classification. Bone Marrow Transplantation. 2008 Jun; 41(2):
S58–64.

2. Nassereddine S, Rafei H, Elbahesh E, Tabbara I. Acute Graft

Versus Host Disease: A Comprehensive Review. Anticancer Res.
2017 Apr 1; 37(4): 1547–55.

3. Lee S-E, Cho B-S, Kim J-H, Yoon J-H, Shin S-H, Yahng S-A, et

al. Risk and prognostic factors for acute GVHD based on NIH
consensus criteria. Bone Marrow Transplant. 2013 Apr; 48(4):

587–92.

4. Gooptu M, Koreth J. Better acute graft-versus-host disease
outcomes for allogeneic transplant recipients in the modern era: a

tacrolimus effect? Haematologica. 2017 May; 102(5): 806–8.

5. Hahn T, Mc Carthy PL, Zhang M-J, Wang D, Arora M, Frangoul

H, et al. Risk Factors for Acute Graft-Versus-Host Disease After

Human Leukocyte Antigen–Identical Sibling Transplants for

Adults With Leukemia. J Clin Oncol. 2008 Dec 10; 26(35): 5728–
34.

6. Stikvoort A, Gaballa A, Solders M, Nederlof I, Önfelt B, Sundberg
B, et al. Risk Factors for Severe Acute Graft-versus-Host Disease

in Donor Graft Composition. Biology of Blood and Marrow

Transplantation. 2018 Mar 1; 24(3): 467–77.
7. Wang F, Cai B, Wang L, Gu Z, Luo L, Wei H, et al. Risk Factors

for Acute Graft-Versus-Host Disease After Allogeneic

Haematopoietic Stem Cell Transplantation: A Single-Center
Experience. Med Sci Monit. 2017 Feb 3; 22: 58–65.

8. Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee

SJ, et al. National Institutes of Health consensus development
project on criteria for clinical trials in chronic graft-versus-host

disease: I. Diagnosis and staging working group report. Biol Blood
Marrow Transplant. 2005 Dec; 11(12): 945–56.

9. Murray J, Stringer J, Hutt D. Graft-Versus-Host Disease (GvHD)

[Internet]. The European Blood and Marrow Transplantation

Textbook for Nurses: Under the Auspices of EBMT [Internet].

Springer; 2017 [cited 2020 Jun 3]. Available from:

https://www.ncbi.nlm.nih.gov/books/NBK543657/
10. Holtan SG, Pasquini M, Weisdorf DJ. Acute graft-versus-host

disease: a bench-to-bedside update. Blood. 2014 Jul 17; 124(3):

363–73.
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of Graft versus Host Disease. Immunol Allergy Clin North Am.

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MCR, Vigorito AC. Acute and chronic Graft-versus-host disease

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500.

Reproduced with permission of copyright owner. Further reproduction
prohibited without permission.

E
D

W
AR

D
S

STEP ONE
Patient’s own cells
are collected
with a skin biopsy.

STEP TWO
Harvested
skin cells are
reprogrammed
into stem cells,
which are then
“guided” to act
like neurons.

STEP THREE
MRI imaging
directs
injection.

STEP FOUR
Reprogrammed
cells are injected
into the brain.

JANUARY/FEBRUARY 202 1 . D ISCOVER 49THE BODY

Researchers test more therapies with novel techniques for a range of diseases.
BY KENNETH MILLER

FOR MORE THAN TWO
decades, experts have
prophesied that stem cells
will someday revolutionize

medicine.
While adult stem cells have long been

used to treat a handful of blood and
immune disorders, the excitement has
centered on two more versatile variet-
ies: embryonic stem cells (ESCs) and
induced pluripotent stem cells (iPSCs),
both of which can be transformed into
any cell type in the body. Google “the
promise of stem cells,” and you’ll get at
least 200,000 hits, involving ailments
ranging from diabetes to neurodegener-
ative disorders. So far, however, no one
has managed to translate that potential
into a practical therapy.

In 2020, a string of breakthroughs
suggested that the revolution may
finally be near. The most dramatic news
came in May, when the New England
Journal of Medicine published the first
case report from a study using custom-
grown stem cells to treat Parkinson’s
disease in humans. The debilitating
condition, which affects 10 million
people worldwide, primarily results
from the loss of neurons that produce
the neurotransmitter dopamine.
Existing treatments have had limited
success. Stem cell researchers aim to
replace dying neurons with healthy ones
grown in the lab — and the NEJM paper
was the clearest sign yet that such efforts
could pay off.

The authors — led by neurosurgeon
Jeffrey Schweitzer at Massachusetts
General Hospital and neurobiologist
Kwang-Soo Kim at McLean Hospital
— used what are known as autologous
iPSCs. These are stem cells generated

from the recipient’s own mature cells,
which greatly reduces the likelihood
that immunosuppressants will be
needed to prevent rejection. The team
collected skin cells from a 69-year-old
man and reprogrammed them into
iPSCs. They then guided the stem
cells to take on the characteristics of
dopaminergic neurons, which they
implanted into the patient’s putamen, a
brain region implicated in Parkinson’s.
Over a 24-month period, PET scans
showed evidence that the new cells were
functional. The man’s motor symptoms
and quality-of-life scores improved,
while his daily medication requirement
decreased. He experienced no side
effects or complications.

“This represents a milestone in
‘personalized medicine’ for Parkinson’s,”
Kim wrote in a statement. It also
represented a milestone for the patient
— George “Doc” Lopez, a physician-
turned-medical equipment entrepre-
neur, whose financial contributions to
Kim’s research helped make the surgery
possible.

Once a record-breaking free-diver,
Lopez had severe tremors and rigidity
before the implant; he could barely rise
from a chair. Afterward,
he was able to return to
swimming and diving,
and to perform such
mundane tasks as tying
his shoes. “Parkinson’s
had me under a death
sentence,” he says. “[The
therapy] has not only
changed my life, it has
literally saved my life.”

Kim cautions that
a single case study is

only a beginning. Much more research,
including full-scale, carefully controlled
clinical trials, will be needed to establish
the safety and efficacy of his team’s tech-
nique. “Nonetheless,” he adds, “I believe
this study is extremely encouraging and
informative.” He and his colleagues plan
to launch such a trial by the end of 2022.
Meanwhile, other human studies using
iPSCs or ESCs are planned or underway
at a handful of medical centers around
the globe.

A “BRIDGE” TO A NEW LIVER
Stem cells also demonstrated lifesaving
powers for a 6-day-old baby in Japan
who received the world’s first successful
transplant of custom-grown liver cells.
The child (whose sex has not been
made public) was born with a urea cycle
disorder, a genetic condition in which
the liver is missing an enzyme that helps
break down nitrogen into urea. Without
it, ammonia builds up in the blood-
stream with potentially fatal results. A
liver transplant is usually needed, but
it can’t be performed until the child is
several months old — which may be too
late. Liver cells called hepatocytes can
sometimes be transplanted as a “bridge

treatment,” but supplies are
scarce in Japan due to low
rates of organ donorship.

Doctors at the
National Center for
Child Health and
Development used
ESCs to grow hepa-
tocytes, then injected
190 million of them
into the baby’s liver. In
May, the team reported
that the transplanted

DAWN OF THE STEM CELL
REVOLUTION?

CH
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STEM CELL
RESEARCHERS
AIM TO REPLACE
DYING NEURONS
WITH HEALTHY
ONES GROWN
IN THE LAB.

50 DISCOVERMAGA ZINE .COM

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cells had kept blood ammonia
levels normal for six months,
until the child received a liver
transplant from its father.

FIXING FAILING HEARTS
Some of this year’s news was
more controversial. In January,
a team led by Osaka University
surgeon Yoshiki Sawa reported
having carried out the first
successful transplant of
iPSC-derived cardiomyocytes
— heart muscle cells — in a
human patient. The recipient,
who had cardiac-muscle dam-
age from a blocked artery, was
implanted with a biodegrad-
able sheet holding 100 million
of the cells as part of a small
clinical trial. The researchers,
who used allogenic iPSCs
derived from a donor’s cells,
planned to monitor the patient
over the next year and eventu-
ally try the procedure on nine
more participants.

In May, however, a Chinese
surgeon disputed that Sawa
was first to perform such a
transplant. Wang Dongjin of
Nanjing Drum Tower Hospital
told the journal Nature that
his team had implanted two

men with cardiomyocytes
derived from allogenic iPSCs
a full year earlier. One patient,
a 55-year-old electrician, said
that before the surgery, he was
constantly tired and out of
breath; now, he could take a
walk, use stairs and sleep for
an entire night.

Aside from which team won
the race, both experiments
leave big question marks.
Although animal studies have
shown promising results for
iPSC-derived cardiomyocytes,
Sawa doesn’t think implanted
cells integrate with a recipi-
ent’s heart tissue. Instead, he
speculates, they may stimulate
healing by releasing growth
factors. If that’s the case,
Sawa’s critics say, it would
be safer to identify those
regenerative proteins and
administer them in a less risky
way, like injection.

Wang’s experiment was
muddied by the fact that
both patients received heart
bypass surgery along with
their new cells. As University
of Washington pathologist
Charles Murry noted in
Nature, “If you do two things
to somebody and they get
better, you can’t say which
one caused it.” D

Doctors used embryonic stem cells,
or ESCs, (left) to grow custom-made
liver cells. Dopaminergic neurons
(right), can be derived from induced
pluripotent stem cells, or iPSCs.

A NEW TECHNIQUE has finally opened up
one of the final frontiers of gene editing:
the mitochondria. These are the mini-
organs that power our cells and have a

little bit of genetic information of their own.
Until now, the gene-editing tool CRISPR didn’t

work inside this part of the cell; CRISPR uses guide
RNA to find its target, but RNA can’t get inside the
mitochondria. Other gene-editing methods have
relied on simply chopping apart mtDNA — the
mitochondria’s DNA — rather than editing it. With this
new tool, chemical biologist David Liu of the Broad
Institute, Harvard University, and Howard Hughes
Medical Institute has found a way to actually change
the mitochondrial genome.

The new editing tool begins with a bacterial toxin
known as DddA, discovered by microbiologist Marcos
de Moraes at the University of Washington School
of Medicine. The toxin kicks off a reaction that turns
one nucleotide — the building blocks of DNA — into
another. When done randomly, the change can be
deadly for a cell. But the researchers were able to
harness this ability to make targeted gene edits.

The end result is “quite a Rube Goldberg-like
protein,” Liu says. The gene editor has many protein
parts, including one that delivers the editor inside the
mitochondria, one that indicates which gene to target
and one that helps increase the efficiency of the edits.
And there’s the toxin itself, which edits the nucleotide.

Key to the process was finding a way to deactivate
the toxin while it passes through the cell, to make
sure it doesn’t do any unintended harm. The team
achieved this by splitting the toxin in half; once inside
the mitochondria, the two parts reform at the site
of the intended gene edit in a process pioneered
by Beverly Mok, a graduate student in Liu’s lab.

The gene editor currently has a few limitations. For
example, it only works on specific nucleotides. Liu
says his lab is studying other toxins that might expand
the editor’s capabilities. He also hopes to improve the
efficiency rate of the edits, which is about 50 percent
at best. Current limitations aside, the tool’s precise
edits will allow scientists to study mitochondrial
diseases in the lab like never before — and perhaps
one day even cure them. D

There’s a mini second
genome inside your cells,
but no one could figure out
how to edit it — until now.
BY NATHANIEL SCHARPING

JA
Y

SM
IT

EDITING THE
MITOCHONDRIA

Study Findings from National Institutes of Health (NIH)
Provide New Insights into Stem Cell Research (Facs-isolation
and Culture of Fibro-adipogenic Progenitors and Muscle Stem
Cells From Unperturbed and Injured Mouse Skeletal Muscle).
Date: Feb. 6, 2023
From: Stem Cell Week
Publisher: NewsRX LLC
Document Type: Article
Length: 486 words

Full Text:
2023 FEB 6 (NewsRx) — By a News Reporter-Staff News Editor at Stem Cell Week — Researchers detail new data in Stem Cell
Research. According to news originating from Bethesda, Maryland, by NewsRx correspondents, research stated, “Fibro-adipogenic
progenitor cells (FAPs) are a population of skeletal muscle-resident mesenchymal stromal cells (MSCs) capable of differentiating
along fibrogenic, adipogenic, osteogenic, or chondrogenic lineage. Together with muscle stem cells (MuSCs), FAPs play a critical
role in muscle homeostasis, repair, and regeneration, while actively maintaining and remodeling the extracellular matrix (ECM).”

Financial support for this research came from National Institutes of Health (NIH) – USA.

Our news journalists obtained a quote from the research from the National Institutes of Health (NIH), “In pathological conditions, such
as chronic damage and muscular dystrophies, FAPs undergo aberrant activation and differentiate into collagen-producing fibroblasts
and adipocytes, leading to fibrosis and intramuscular fatty infiltration. Thus, FAPs play a dual role in muscle regeneration, either by
sustaining MuSC turnover and promoting tissue repair or contributing to fibrotic scar formation and ectopic fat infiltrates, which
compromise the integrity and function of the skeletal muscle tissue. A proper purification of FAPs and MuSCs is a prerequisite for
understanding the biological role of these cells in physiological as well as in pathological conditions. Here, we describe a
standardized method for the simultaneous isolation of FAPs and MuSCs from limb muscles of adult mice using fluorescence-
activated cell sorting (FACS). The protocol describes in detail the mechanical and enzymatic dissociation of mononucleated cells
from whole limb muscles and injured tibialis anterior (TA) muscles. FAPs and MuSCs are subsequently isolated using a semi-
automated cell sorter to obtain pure cell populations.”

According to the news editors, the research concluded: “We additionally describe an optimized method for culturing quiescent and
activated FAPs and MuSCs, either alone or in coculture conditions.”

This research has been peer-reviewed.

For more information on this research see: Facs-isolation and Culture of Fibro-adipogenic Progenitors and Muscle Stem Cells From
Unperturbed and Injured Mouse Skeletal Muscle. Journal of Visualized Experiments, 2022(184). Journal of Visualized Experiments
can be contacted at: Journal of Visualized Experiments, 1 Alewife Center, Ste 200, Cambridge, MA 02140, USA.

The news correspondents report that additional information may be obtained from Giulia Riparini, Niamsd, Lab Muscle Stem Cells &
Gene Regulat, National Institutes of Health (NIH), Bethesda, MD 20892, United States. Additional authors for this research include
Vittorio Sartorelli and James M. Simone.

Keywords for this news article include: Bethesda, Maryland, United States, North and Central America, Stem Cell Research, National
Institutes of Health (NIH).

The citation for this news report is: NewsRx. Study Findings from National Institutes of Health (NIH) Provide New Insights into Stem
Cell Research (Facs-isolation and Culture of Fibro-adipogenic Progenitors and Muscle Stem Cells From Unperturbed and Injured
Mouse Skeletal Muscle). Stem Cell Week. February 6, 2023; p 1523.

http://www.newsrx.com/newsletters/Stem-Cell-Week.html
Source Citation (APA 7th Edition)
Study Findings from National Institutes of Health (NIH) Provide New Insights into Stem Cell Research (Facs-isolation and Culture of

Fibro-adipogenic Progenitors and Muscle Stem Cells From Unperturbed and Injured Mouse Skeletal Muscle). (2023). Stem Cell
Week, 1523. https://link.gale.com/apps/doc/A735942901/GPS?u=lirn50909&sid=bookmark-GPS&xid=bfd13dc9

Gale Document Number: GALE|A735942901

http://www.newsrx.com/newsletters/Stem-Cell-Week.html

October 2019 VOL. 47, NO. 10 UrologyTimes.com Expert clinical analysis. Practice advice. Policy perspectives.

OAB/INCONTINENCE
Clinical Updates: Low
testosterone, incontinence may
be linked in older women

BLADDER CANCER
Clinical Updates: Cystoscopy
overuse common in bladder Ca
surveillance

PROSTATE CANCER
Clinical Updates: Real-
world outcomes reported for
sipuleucel-T

Stone recurrence: What
practitioners should know

Q&A

Juan Calle, MD

Management of stone recurrence presents a valuable
opportunity for clinicians to help prevent stone patients
from suffering additional attacks. In this interview,
Juan Calle, MD, discusses how he follows patients
once they are stone free, dietary/lifestyle modifi-
cation and medical management, and advice
for young urologists looking to become
experts in stone recurrence.

For the full article, please turn to page 37

How has urologists’
management of BPH
patients changed?
Is TURP still the gold standard for treatment
of lower urinary tract symptoms associated
with BPH? How are urologists using new sur-
gical treatments, and how have these modal-
ities changed the patient workup? Urology
Times asked randomly selected urologists
how their management of BPH has changed
in recent years.

KIDNEY STONES

For their responses, please turn to page 44

BPHSpeak Out Inside

SEXUAL DYSFUNCTION

Cell-based therapies may eventually be used
to modify ED, other diseases, but not yet

Stem cells pose risk,
offer promise

Patients with urologic conditions
have easy access to stem cell ther-
apy options offered by a spectrum
of providers at locations that vary

from strip mall clinics to academic centers.
But while there’s hope that cell-based ther-

apies might not only treat symptoms but also
modify diseases, including erectile dysfunction,

the scientific evidence to show therapies using any
stem cells work and don’t cause harm is lacking.

The FDA warns that unapproved stem cell therapies
can be harmful and may be illegal and unproven (bit.ly/

FDAstemcell). The agency has tried to regulate stem cell
clinics as part of a comprehensive move to oversee regen-
erative medicine products. In May, for example, the FDA
announced it was seeking permanent injunctions to stop
Cell Clinic of Sunrise, FL, and California Stem Cell Treat-
ment Center, with locations throughout the state, to stop
marketing stem cell products without FDA approval and for
deviating from good manufacturing practice requirements.

Providers at the California clinic were injecting cancer
patients’ tumors with stem cells from their fat.

“The product was then administered to cancer patients
with potentially compromised immune systems and for
whom the vaccine posed a potential for harm, including
the possibility of inflammation and swelling of the heart
and surrounding tissues,” the FDA said in a statement.

As recently as early September, the FDA sent a warning
letter to Stemell, of San Juan Capistrano, CA, for “manu-
facturing and distributing unapproved products derived
from umbilical cord blood and umbilical cord and for
significant deviations from current good tissue practice

Lisette Hilton / UT Correspondent

See STEM CELLS, on page 39

STEM CELL TYPES / Photos from top: Multipotential stem
cells in placenta and amniotic fluid can be differentiated into heart muscle
and liver cells, among other cell types; induced pluripotent stem cells are
differentiated into nerve cells; pre-adipocytes isolated from the stromal
vascular fraction. (Photos courtesy of the Wake Forest Institute for Regenerative Medicine)

Cover Feature

OCTOBER 2019 ∣ Urology Times ∣ 39

(CGTP) and current good manufacturing prac-
tice (CGMP) requirements… creating potential
significant safety concerns that put patients at
risk.”

About 15% of the 169 stem cell clinics that were
the subject of a recent report on the direct-to-con-
sumer stem cell business in the southwest U.S.
offered treatments for urologic conditions, includ-
ing erectile dysfunction, interstitial cystitis, Pey-
ronie’s disease, and bladder and kidney conditions
(Stem Cell Reports 2019; 13:247-53).

“What we found was that clinics treating uro-
logic conditions almost always treated a whole
set of other conditions too that were not urologic
in nature,” said the report’s first author, Emma
K. Frow, PhD, assistant professor in the School
for the Future of Innovation in Society and the
School of Biological and Health Systems Engi-
neering at Arizona State University, Tempe.

Only one, and possibly two, urologists were
among the providers at the 169 clinics, according
to the report.

The ThriveMD clinic in Denver and Vail, CO
is one stem cell clinic offering urologic services.
Scott Brandt, MD, the clinic’s medical director,
trained as an anesthesiologist. Dr. Brandt treats
joint and back pain, as well as erectile dysfunc-
tion. He uses adipose-derived stem cells for ED,
according to the ThriveMD website.

“Besides adipose-derived cells, additional stem
cells and growth factors are sourced from bone
marrow concentrate,” according to the site. Dr.
Brandt did not respond to Urology Times’ request
for comment.

Hundreds if not thousands of clinical trials are
currently looking at stem cell use in medicine,
according to Dr. Frow, but there are no FDA-ap-
proved stem cell products for conditions in urol-
ogy and many other specialties.

Not only are stem cell procedures not yet
approved in urology and other specialties, but
there’s confusion among patients and providers
about what stem cell therapies are, according to
Anthony Atala, MD, professor of urology and
regenerative medicine at Wake Forest School
of Medicine, Winston-Salem, NC.

Platelet-rich plasma (PRP), for example, is a
cell therapy—not a stem cell therapy.

“In reality, PRP is one of the very few treat-
ments right now that can be used without FDA
approval, and is being used,” Dr. Atala said.

Among the stem cell sources being studied are
fat-derived stem cells and bone marrow-derived
stem cells, which are autologous stem cells that
providers harvest from patients and inject back
into those patients in the same setting.

“The area in urology where those are being most
used is in erectile dysfunction,” Dr. Atala said.

Researchers have found that a big challenge
with using fat- and bone marrow-derived stem
cells is that they don’t last when they’re reinjected.

“Basically, most of those cells are gone within
a day after injection, and all the cells are gone
within 5 days,” Dr. Atala said. “Longitudinal,
well-controlled studies still need to be done to
see what the long-term effects are from therapies
using these cells that really don’t stay around.”

Researchers who tracked stem cells derived
mostly from bone marrow, adipose tissue, or
skeletal muscle and intracavernously injected
them into the penis found the stem cells escaped
the penis and went into bone marrow, and it
wasn’t clear what happened after that (Stem Cells
Dev 2012; 21:343–51).

Another drawback of using fat- and bone mar-
row-derived stem cells is that they are limited in
their ability to differentiate into other cell types
and their ability to be grown and expanded to
large quantities, according to Dr. Atala.

Stem cells derived from muscle tissue do last.
Researchers are studying muscle-derived stem
cells for conditions like urinary incontinence,
according to Dr. Atala.

But long-term research is limited on mus-
cle-derived stem cells, he said.

Cord blood stem cells are yet another type of
autologous stem cell. Cord blood cells, retrieved
at birth, are stored for later use.

“Those are very similar in use to bone mar-
row-derived stem cells,” Dr. Atala said. “Like
bone marrow cells, cord stem cells cannot be
expanded very well and they cannot be converted
to many other tissue types.”

The ideal stem cell should differentiate read-
ily and expand to large quantities, which would
make it easier to treat patients as many times
as needed or at multiple sites. Although human
embryonic stem cells and induced pluripotent

stem cells have these properties, their major
challenge lies in their potential to form tumors.

“Embryonic stem cells come from a discarded
embryo. And induced pluripotent stem cells are
from adult cells that can be reverted back to an
embryonic-like cell by using specific genes or
factors,” Dr. Atala said. Both cell types can be
expanded rapidly and are usable in any tissue
type, including liver, heart, and cartilage.

Because embryonic stem cells and induced
pluripotent stem cells may form tumors, their
translation to the clinical setting has been slow.

Amnion cells, which are from the placenta and
amniotic fluid, are another stem cell type that
differentiate, expand, and don’t form tumors.

“It’s a good cell type, but no cell is perfect,” Dr.
Atala said. “One of the challenges with amnion
cells is you have to work harder to drive them.
With a human embryonic stem cell or an induced
pluripotent stem cell, it only takes 7 days to con-
vert those cells to liver cells. It takes 20 days to
convert amnion stem cells to liver cells. However,
that’s also the same property that does not allow
the cells to form the tumors, because you get the
cells a little bit later in terms of development.”

At the end of the day, scientists and physicians
don’t know what any of these cells will do for
patients long term, according to Dr. Atala.

“There are almost no longitudinal, prospec-
tive, randomized, controlled, double-blinded,
long-term studies and therefore a lot of these
therapies need to go through that process before
they should be offered to patients outside the
research setting,” Dr. Atala said.

A position statement by the Sexual Medicine
Society of North America agrees that, until the

STEM CELLS
continued from page 1

Irwin Goldstein, MD, says scientific literature shows
low-intensity shock wave therapy works by attracting
stem cells to the penis and by promoting neo-angiogen-
esis. (Photo courtesy of San Diego Sexual Medicine)“What we found was that clinics

treating urologic conditions
almost always treated a whole

set of other conditions
too that were not
urologic in nature.”

EMMA K. FROW, PhD

“Longitudinal, well-controlled
studies still need to be done to
see what the long-term effects

are from therapies using
these cells that really
don’t stay around.”

ANTHONY ATALA, MD

See STEM CELLS, on page 40

Cover Feature

FDA approves stem cell, PRP, or shock wave ther-
apy for erectile dysfunction, use of these therapies
is experimental and should be conducted under
research protocols in compliance with Institutional
Review Board approval (bit.ly/SMSNAposition).

Clinicians who retrieve adipose-derived stem
cells and inject them into the penis to improve sex-
ual function are providing unproven treatments
and subjecting patients to potential risks, accord-
ing to Peter Stahl, MD, director of male reproduc-
tive and sexual medicine at New York-Presbyteri-
an Hospital/Columbia University Medical Center.

“It may be in the future that some of those
therapies will emerge clinically effective, but at
least to my knowledge at this point in time in
late 2019 there is no evidence basis for injection
of stem cells into the penis to promote erectile

function,” Dr. Stahl said. “That being said, there
has been a really widespread dissemination and
utilization of stem cell-based techniques to pro-
mote and improve sexual function in men despite
the lack of evidence. It’s a problem.”

Urologist Koushik Shaw, MD, of Austin Urol-
ogy Institute in Austin, TX, said patient demand
and the concern that patients are going to non-uro-
logic providers for unproven stem cell treatments
is putting pressure on urologists like him to look
into offering the therapies. While Dr. Shaw said he
offers shock wave treatment for erectile dysfunc-
tion but no stem cell treatments, he is considering
offering PRP if supported by clinical studies.

“I think it all has to be done with informed con-
sent, with eyes wide open. Make sure the patient
understands it’s not FDA approved, studies are lim-
ited, and the expectation should be limited,” Dr.
Shaw said. “In our city, we have a plastic surgeon
and ER physicians who offer shock wave therapy
for erectile dysfunction. I see med spas doing it.
The whole men’s health movement is ours to lose.”

Stem cell therapies are a different matter,
according to Leigh Turner, PhD, associate
professor at the Center for Bioethics, School
of Public Health and College of Pharmacy at
University of Minnesota, Minneapolis. Urolo-
gists and others who are concerned with being
compliant and operating within evidence-based
medical practice should consider steering clear
of administering stem cell products, unless it’s
in a research setting, according to Dr. Turner.

“And it’s not clear whether down the road these
are going to be evidence-based therapies,” said Dr.
Turner. A 2016 paper that he co-authored found
more than 50 of the 351 U.S. businesses engaged in
direct-to-consumer marketing of stem cell inter-
ventions offered urologic services. Urologic con-
ditions ranked seventh most common among 29
marketed conditions (Cell Stem Cell 2016; 19:154-7).

Dr. Turner called this risky terrain for urologists.
“They run the risk of violating federal law. If

it’s a licensed medical practitioner, people could
get in trouble with their state medical boards or
the Federal Trade Commission,” Dr. Turner said.

For now, there are less risky and promising stem
cell-like approaches to conditions such as erectile
dysfunction. One is not to inject stem cells but rath-
er attract stem cells to the penis with low-intensity
shock wave therapy, according to Dr. Stahl.

“There’s a fairly large body of basic scientific lit-
erature indicating that low-intensity shock wave
therapy works by attracting stem cells to the penis
and by promoting neo-angiogenesis,” Dr. Stahl said.

Providing the therapy involves using an FDA-
cleared device with “genuine” shock waves, accord-
ing to Irwin Goldstein, MD, a urologist who prac-
tices sexual medicine in San Diego and and is direc-
tor of the nonprofit Institute for Sexual Medicine
(SexualMed.org).

“There are a lot of imitation non-shock wave
acoustic sound waves that are being scammed and
sold to patients who are desperate,” said Dr. Gold-
stein, who uses a device known as the UroGold
100. “Real shock wave therapy has been shown to
activate endogenous stem cells. This specific device
is FDA cleared now in the U.S. for increasing blood
flow, connective tissue activation, and amelioration
of pain, and the FDA has classified this device a
non-significant risk (NSR) to humans.”

He said he has recruited patients for a pro-
spective sham-controlled trial he will conduct
looking at shock wave therapy with the UroGold
100 device for erectile dysfunction.

Pursuing evidence-based research on stem cell
and other therapies for male sexual function is
needed, according to Dr. Goldstein, who also
offers PRP for erectile dysfunction.

“The construct of erectile dysfunction man-
agement by symptomatic treatment… is what
we’ve mostly ever had,” he said. “But now with
shock wave therapy, PRP, and one day maybe
stem cells, the idea is having a disease modifi-
cation strategy.

“It is the first time in erectile dysfunction his-
tory that we might change a primary underlying
pathology and make the situation more responsive
to symptomatic treatment or to where the person
doesn’t even need symptomatic treatment.”

Dr. Turner filed an expert opinion report in a lawsuit
filed against The Lung Institute, which markets pur-
ported stem cell treatments for lung diseases. Dr. Gold-
stein’s practice is a site for a trial sponsored by Tissue
Genesis that uses stem cells for erectile dysfunction.UT

STEM CELLS
continued from page 39

40 ∣ Urology Times ∣ OCTOBER 2019

“At this point in time in late
2019 there is no evidence basis
for injection of stem cells into

the penis to promote
erectile function.”

PETER STAHL, MD

“The whole men’s
health movement is
ours to lose.”

KOUSHIK SHAW, MD

“[Providers of stem cell
interventions] run the risk
of violating federal law.”

LEIGH TURNER, PhD

Embryonic stem cells

�Able to differentiate

�Able to expand to large
quantities

�May form tumors

Induced pluripotent stem cells

�Able to differentiate

�Able to expand to large
quantities

�May form tumors

Amnion cells

�Able to differentiate

�Able to expand to large
quantities

�Does not form tumors

�Takes longer than embryonic
or induced pluripotent stem
cells to covert to other cells

Cord blood stem cells

�Autologous

�Limited ability to
differentiate

�Limited ability to expand
to large quantities

Bone marrow and fat stem cells

�Autologous

�Last only up to 5 days when
reinjected

�Limited ability to differentiate

�Limited ability to expand to
large quantities

STEM CELL TYPES AT A GLANCE

MOST PRIMITIVE/MOST POWERFUL MOST MATURE/LEAST POWERFUL

Source: Anthony Atala, MD

42 antiaging
DermatologyTimes®June 2020

Quick TAKES

More research is needed to clarify that role of stem
cell factor in development of common benign
and malignant conditions.

Researchers found that stem cell factor was
positively expressed in all melasma, solar
lentigines and freckled lesions.

Stem cell factor plays an
important role in the development
hyperpigmentation disorders.

Stem cell factor plays role
in hyperpigmented skin
LISETTE HILTON | Staff Correspondent

S tem cell factor, a growth factor critical for
melanocyte survival, plays an import-
ant role in the development of benign and
malignant skin hyperpigmentation dis-

orders. More research is needed to look at tar-
geting stem cell factor inhibition as a way to treat
skin lesions from melasma to melanoma, accord-
ing to an article published December 2019 in the
Asian-Pacific Journal of Cancer Prevention.1

Stem cell factor binds to the receptor tyrosine
kinase and is expressed by the body’s fibroblasts
and endothelial cells, promoting melanocyte dif-
ferentiation proliferation, migration and survival,
according to the authors.

“The interaction of stem cell factor with its
receptor, c-kit, is well known to be crucial for the
survival of melanocytes,” the researchers write.
But little is known about the role of stem cell fac-
tor/c-kit interaction in epidermal pigmentation,
according to the paper.

These researchers studied stem cell factor
expression in benign and malignant pigmented
lesions to determine the growth factor’s role in
pathogenesis and potential use as a therapeutic
target.

They studied stem cell factor expression in
60 patients with benign hyperpigmented lesions,
including 20 with melasma, 20 with solar lentigines
and 20 with freckles. They also studied 36 patients

with hyperpigmented skin cancers, including 14
with basal cell carcinoma, 12 with squamous cell
carcinoma and 10 who had malignant melanoma.

They found stem cell factor was positively
expressed in all melasma, solar lentigines and
freckled lesions.

More specifically, immunohistochemical test-
ing revealed significantly higher stem cell factor
expression in melasma lesions than in perile-
sional skin. They found moderate expression in
60% and strong expression in 40% of melasma
cases in melasma lesions. While there was only
weak expression in 100% of melasma cases in
perilesional areas.

The intensity of stem cell factor expression
in lentigines lesions was weak in 10%, moderate
in 30% and strong in 60% of cases, while perile-
sional areas in those cases had no stem cell factor
expression in 20% of patients and weak expres-
sion in 80%.

Stem cell factor expression intensity was
increased in the lesional parts of freckles cases,
with weak expression in 20% of patients, moder-
ate in 30% and strong expression in 50%. Stem
cell factor was not expressed in 20% of perile-
sional areas in patients with freckles, weakly
expressed in 70% and moderately expressed in
10% of perilesional areas.

Stem cell factor expression was significantly

higher in basal cell carcinoma tumor cells com-
pared with normal surrounding keratinocytes.
The researchers found the squamous cell carci-
noma cases they studied showed 50% cytoplas-
mic positivity for stem cell factor expression, sug-
gesting stem cell factor is implicated in squamous
cell carcinoma pathogenesis. Stem cell factor was
also positively expressed in malignant melanoma.

While basal cell carcinoma, squamous cell
carcinoma and malignant melanoma showed var-
iable intensities of cytoplasmic expression of stem
cell factor, the increase in expression in basal cell
carcinoma and melanoma tumor cells was statis-
tically significant, the authors write.

The researchers concluded their findings
strongly suggest stem cell factor plays a key role in
the development of common benign and malig-
nant skin hyperpigmented disorders, but more
research is needed to clarify that role. Studies
looking at using stem cell factor as a target for
developing new treatments for hyperpigmented
disorders and malignancies also are needed.
Disclosures:
The authors report no conflicts of interest, according to the paper.

Reference:
1 Atef A, El-Rashidy MA, Abdel Azeem A, Kabel AM. The Role of Stem Cell Fac-

tor in Hyperpigmented Skin Lesions. Asian Pac J Cancer Prev. 2019 Dec
1;20(12):3723-3728.

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st

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DT0620_042-043_045_AntiAging.indd 42DT0620_042-043_045_AntiAging.indd 42 5/28/20 2:49 PM5/28/20 2:49 PM

researchupdate
H E A T H E R B U S C H M A N , P H D

16 | PN March 2020

Stroke Drug Boosts
Stem Cell Therapy
Four months after treating his
rats, Yasuhiro Shiga, MD, PhD, checked
on them.

Walking into the lab, Shiga, a visit-
ing scholar at the University of Califor-
nia (UC) San Diego School of Medicine
in San Diego, carried minimal expecta-
tions. Treating spinal-cord injuries (SCI)
with stem cells had been tried by many
people, many times before, with modest
success at best.

The endpoint he was specifically
there to measure — pain levels —
hadn’t seemed to budge in past efforts.

“Well, it doesn’t seem to be work-
ing. I don’t see any real change in pain
behavior in any of the groups,” Shiga
recalls saying, apologetically, as he
walked into the office of his supervisor,
Wendy Campana, PhD, professor in the
Department of Anesthesiology and Pro-
gram in Neuroscience. But to Campa-
na’s surprise, Shiga continued, almost
as an after-thought, “although … some
rats are actually really moving.”

The difference for those rats was
this: Before delivering them into the SCI
site, Shiga and Campana had condi-
tioned stem cells with a modified form
of tissue-type plasminogen activator
(tPA), a drug commonly used to treat
nonhemorrhagic stroke.

Their findings were published Dec.
17 in Scientific Reports.

Big Improvements
The drug tPA is used to break up blood
clots, allowing blood to more freely flow
back into the brain following a stroke.

But tPA is also a naturally occurring
enzyme known to boost neuron growth
and dampen inflammation.

So the researchers used an enzy-
matically inactive form of tPA, still anti-
inflammatory and pro-neuron growth
but without effects on blood clotting,

which could be a dangerous side effect
in a person not having a stroke.

In a laboratory dish, the research-
ers added the modified tPA to neural
progenitor cells — the precursors to

neurons. They had generated these pre-
neurons from induced pluripotent stem
cells, a special kind of stem cell that can
be derived from a person’s skin cells.

After 15 minutes, the researchers
transferred either tPA-conditioned or
unconditioned neural progenitor cells to
the injury site in a rat model of severe SCI.

Two months after treatment, the
researchers found 2.5-fold more tPA-
conditioned neural progenitor cells
than unconditioned cells still present
in the rats. What’s more, the tPA-con-
ditioned cells had begun specializing
into full-fledged neurons, with axons
(branches) emerging from the site of
transplantation and extending as far
as four vertebrae away. According to
Campana, that’s unusual.

“It was striking to see at two and
four months the tremendous improve-
ments in the ability of those progenitor
cells to survive in the injury cavity,” she
says. “Just keeping these cells alive has
been very difficult in past studies.”

Even more surprisingly, it turned
out that what Shiga had observed in the

rats with modified tPA was a three-fold
increase in motor activity after four
months, as measured using a well-
established scoring system that quanti-
fies a combination of rat joint and limb

movements, trunk stability, paw and tail
positioning, stepping and coordination.

Pain is a special focus of Campana’s
lab, and the team was initially most
interested in that aspect of SCI treat-
ment. They measure pain in rat models
based on how they lift their front paws in
response to added weights.

“The addition of tPA-treated
neural precursors didn’t reduce pain
in this model,” Campana says. “But
we also didn’t exacerbate it — and to
not see increased pain is important
safety information for clinical trans-
lation to improve motor outcomes.
We also don’t want worsen the pain
burden of patients living with spinal-
cord injuries.”

One limitation of this SCI model
is that the rats don’t live long enough
to truly recapitulate what for humans
is a long-term condition — or long
enough to measure potential changes
in gene expression over time. But it
is currently the best available non-
human primate model for the human
situation, Campana says.

In this microscopic view of rat spinal-cord injury models, there is an abundance of

neural progenitor cell-derived axons emerging when the cells are preconditioned with a

modified stroke drug, right, compared to those that received unconditioned cells, left.

COURTESY OF THE UNIVERSITY OF CALIFORNIA SAN DIEGO

016_PN_March_2020.indd 16 2/5/20 11:30 AM

creo

March 2020 PN | 17

Additional Studies
While Campana’s work may be many
years away from testing in patients,
her approach has two potential advan-
tages compared to other studies.

First, the use of induced pluripotent
stem cells means a patient’s own cells
would be the source of treatment, rather
than a transplant of donated cells from
another person. Second, tPA is already
approved by the Food and Drug Admin-
istration (FDA) for use in humans.

The team next plans to dive into
exactly what modified tPA does to
neural progenitor cells on a molecu-
lar level that stimulates their growth
and allows them to help repair SCIs.

Meanwhile, other UC San Diego
School of Medicine researchers are

testing other approaches to treating
SCI with stem cells in clinical trials.
For example, in June 2018, a team
reported that a first-in-human phase
1 clinical trial in which neural stem
cells were transplanted into par-
ticipants with chronic SCI produced
measurable improvement in three
of four subjects, with no serious
adverse effects.

There are currently an estimated
291,000 people living with SCI in the
U.S. and approximately 17,730 new
cases each year, according to 2019 sta-
tistics provided by the National Spinal
Cord Injury Statistic Center at the Uni-
versity of Alabama at Birmingham.

There are no FDA-approved stem
cell-based therapies available for SCI.

Additional co-authors in this
research include: Akina Shiga; Seiji
Ohtori, Chiba University; Pinar Mesci;
HyoJun Kwon; Coralie Brifault; John
H. Kim; Jacob J. Jeziorski; Chanond
Nasamra; Alysson R. Muotri; and Ste-
ven L. Gonias, UC San Diego.

The research was funded, in
part, by the National Institutes of
Health, Department of Defense,
International Rett Syndrome Foun-
dation and National Cooperative
Reprogrammed Cell Research
Groups to Study Mental Illness.

Heather Buschman, PhD, is a
senior public information officer at
UC-San Diego Health. n

016_PN_March_2020.indd 17 2/5/20 11:30 AM

creo

016

017

Oyat et al. BMC Psychology (2022) 10:284
https://doi.org/10.1186/s40359-022-00998-z

RESEARCH

The psychological impact, risk factors
and coping strategies to COVID-19 pandemic
on healthcare workers in the sub-Saharan Africa:
a narrative review of existing literatu

Freddy Wathum Drinkwater Oyat1, Johnson Nyeko Oloya1,2, Pamela Atim1,3, Eric Nzirakaindi Ikoona4,
Judith Aloyo1,5 and David Lagoro Kitara1,6,7*

Abstract

Background: The ongoing COVID-19 pandemic has significantly impacted the physical and mental health of the
general population worldwide, with healthcare workers at pa

icular risk. The pandemic’s effect on healthcare workers’
mental well-being has been characterized by depression, anxiety, work-related stress, sleep disturbances, and post-
traumatic stress disorder. Hence, protecting the mental well-being of healthcare workers (HCWs) is a considerable
priority. This review aimed to determine risk factors for adverse mental health outcomes and protective or coping
measures to mitigate the harmful effects of the COVID-19 crisis among HCWs in sub-Saharan Africa.

Methods: We performed a literature search using PubMed, Google Scholar, Cochrane Library, and Embase for
relevant materials. We obtained all articles published between March 2020 and April 2022 relevant to the subject of
review and met pre-defined eligibility criteria. We selected 23 articles for initial screening and included 12 in the final
review.

Result: A total of 5,323 participants in twelve studies, predominantly from Ethiopia (eight studies), one from Uganda,
Cameroon, Mali, and Togo, fulfilled the eligibility criteria. Investigators found 16.3–71.9% of HCWs with depressive
symptoms, 21.9–73.5% with anxiety symptoms, 15.5–63.7% experienced work-related stress symptoms, 12.4–77%
experienced sleep disturbances, and 51.6–56.8% reported PTSD symptoms. Healthcare workers, working in emer-
gency, intensive care units, pharmacies, and laboratories were at higher risk of adverse mental health impacts. HCWs
had deep fear, anxious and stressed with the high transmission rate of the virus, high death rates, and lived in fear of
infecting themselves and families. Other sources of fear and work-related stress were the lack of PPEs, availability of
treatment and vaccines to protect themselves against the virus. HCWs faced stigma, abuse, financial problems, and
lack of support from employers and communities.

Conclusion: The prevalence of depression, anxiety, insomnia, and PTSD in HCWs in sub-Saharan Africa during the
COVID-19 pandemic has been high. Several organizational, community, and work-related challenges and interven-
tions were identified, including improvement of workplace infrastructures, adoption of correct and shared infection

© The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which
permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the
original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or
other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line
to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory
regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this
licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco
mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Open Acces

*Correspondence: klagoro2@gmail.com

6 Faculty of Medicine, Department of Surgery, Gulu University, P.O. Box 166,
Gulu City, Ugand

Full list of author information is available at the end of the article

http://orcid.org/0000-0001-7282-5026

http://creativecommons.org/licenses/by/4.0/

http://creativecommons.org/publicdomain/zero/1.0/

http://crossmark.crossref.org/dialog/?doi=10.1186/s40359-022-00998-z&domain=pdf

Page 2 of 16Oyat et al. BMC Psychology (2022) 10:284

Introduction
When coronavirus disease 2019 (COVID-19) was
declared a pandemic in March 2020, healthcare work-
ers (HCWs) globally and in sub-Saharan Africa (SSA)
were unprepared for the scale of the physical and men-
tal health devastation that was to follow [1]. The impact
of the COVID-19 pandemic on healthcare workers has
been profound, characterized by death, disability, and
untenable burden on mental health and well-being [2].
Factors impacting their mental health include high risks
of exposure and infection, financial insecurity, separa-
tion from loved ones, stigma, difficult triage decisions,
stressful work environment, scarcity of supplies includ-
ing personal protective equipment (PPEs), exhaus-
tion, traumatic experiences due to regular witnessing of
deaths among patients and colleagues [2, 3]. Greenberg
et al. [4] observed that the COVID-19 pandemic put
healthcare professionals worldwide in an unprecedented
situation, making difficult decisions to provide care for
many severely ill patients with constrained or inadequate
resources.

In almost all WHO regions, data indicates that infec-
tion rates among healthcare workers are higher than in
the general population [5]. Scholars suggest that the
end of the COVID-19 pandemic is not yet in sight. Nei-
ther are they sure about the virulence of the following
variant when it appears as caseloads are still rising, with
more than 621 million infections and 6.5 million deaths
reported worldwide by 19th October 2022 [6]; mainly
driven by the newer omicron variants. However, recently
in October 2022, we received with gratitude a reassur-
ing message from US President Biden declaring the
end of the COVID-19 pandemic in the United States of
America.

Meanwhile, previous studies found high levels of
depression, anxiety, and PTSD in survivors among the
general population and healthcare workers (HCWs) one-
to-three years after the control of the SARS epidemic [7]
and the 2014–2016 Ebola epidemic in West Africa [8]. In
addition, recent surveys [9–14], reviews, and meta-analy-
ses [15–18] are pointing to early evidence that a consider-
able proportion of healthcare workers have experienced
stress, anxiety, depression, and sleep disturbances during
the COVID-19 pandemic, raising concerns about risks to
their long-term mental health.

Studies from the global north countries [19, 20], UK
[21], USA [22], and in India [23], and China [24, 25]
have shed light on the vulnerability that characterizes
frontline healthcare workers during this pandemic,
especially regarding their mental health and well-being.
However, evidence in sub-Saharan Africa is scanty, and
the pattern and prevalence of psychological disorders
are not well understood.

Evidence from a systematic review by Pappa S et al.
on 33,062 Chinese HCWs in April 2020 found a pooled
prevalence rate of mental health problems among
respondents; anxiety 23.2%, depression 22.8%, and
insomnia 38.9% [26]. Similarly, Singapore study, Tan
et al. [27], Li et al. [28], BMA [29] and in China [31]
found high levels of psychological disorders among
health workers.

Since the beginning of the pandemic, we found one
systematic review involving 919 frontline HCWs, 3928
general HCWs, and 2979 medical students conducted
in Africa from December 2019 to April 2020 [31].
The study by Chen J et al. reported a high prevalence
of depression, anxiety, and insomnia among front-
line HCWs in sub-Saharan Africa (SSA) at 45%, 51%,
and 28%, respectively. In comparison, the prevalence
of depression, anxiety, and insomnia among the gen-
eral population was much lower at 30%, 31%, and 24%,
respectively [31]. Furthermore, we found that only a
few studies investigated protective and coping meas-
ures, given the many uncertainties surrounding the
evolution of the COVID-19 pandemic [32]. Adequate
data are needed to equip frontline HCWs and health-
care managers in sub-Saharan Africa to mitigate the
medium and long-term adverse effects of the COVID-
19 pandemic [33].

This review aimed to answer three questions (1) What
is the psychological impact of the COVID-19 pandemic
on HCWs in Sub-Saharan Africa?

(2) What are the associated risk factors during the
COVID-19 pandemic?

(3) What interventions (mitigating and coping strate-
gies) protect and support the mental health and well-
being of HCWs during the ongoing crises and after the
pandemic?

control measures, provision of PPEs, social support, and implementation of resilience training programs. Setting up
permanent multidisciplinary mental health teams at regional and national levels to deal with mental health and pro-
viding psychological support to HCWs, supported with long-term surveillance, are recommended.

Keywords: COVID-19 pandemic, Social support, Occupational health and safety, Mental health surveillance,
Workplace organization

Page 3 of 16Oyat et al. BMC Psychology (2022) 10:284

Methodology
Search methodology and article selection
This current article is a mixed-method narrative review
of existing literature on mental health disorders, risk
factors, and interventions relevant to the COVID-19
pandemic on HCWs in sub-Saharan. A search on the
PubMed electronic database was undertaken using the
search terms “novel coronavirus”, “COVID-19”, “nCoV”,
“mental health”, “psychiatry”, “psychology”, “anxiety”,
“depression” and “stress” in various permutations and
combinations.

Search process

We conducted a comprehensive literature search on
original articles published from March 2020 to 30
April 2022 in electronic databases of Embase, PubMed,
Google Scholar, and the daily updated WHO COVID-
19 database. Our search terms included but were not
limited to (’COVID-19’/exp OR COVID-19 OR ’coro-
navirus’/exp OR coronavirus) AND (’psychological’/
exp OR psychological OR ’mental’/exp OR mental
OR ’stress’/exp OR stress OR ’anxiety’ OR anxiety OR
’depression’ OR depression OR ’post-traumatic’ OR
’post-traumatic’/exp OR ’trauma’ OR ’trauma’/exp)
OR Health care workers, medical workers of health
care professionals, sub-Saharan Africa, for Embase.
(“COVID-19” [All Fields] OR “coronavirus” [All Fields])
AND (“Stress, Psychological” [Mesh] OR “mental”
OR “anxiety” OR “depression” OR “stress” OR “post-
traumatic” OR “trauma”) for PubMed, for the WHO
COVID-19 database, and (“COVID-19” OR “coronavi-
rus”) AND (“Psychological” OR “mental” OR “anxiety”
OR “depression” OR “stress” OR “post-traumatic” OR
“trauma”) for Google Scholar. On reviewing the above
citations, twelve articles met the inclusion criteria rel-
evant for this review and are in Table 1. All twelve arti-
cles were cross-sectional, with one qualitative and the
others quantitative observational studies.

Eligibility criteria
We included original qualitative and quantitative stud-
ies examining the risk factors, psychological impact of
COVID-19 and coping strategies of healthcare workers
(HCWs) in sub-Saharan Africa during the COVID-19
pandemic. We excluded studies if they were.

1. Not reported in the English language 2. Studies
which were not primary research 3. Studies that had
not been published in a peer-reviewed journal 4. Stud-
ies that did not include data on HCWs’ mental health
or psychological well-being 5. Duplicate studies 6. not
using validated instruments to measure the risks and
psychological impact.

FWDO performed the search of articles. DLK
reviewed the articles involving screening of titles, fol-
lowed by examination of abstracts. The potential arti-
cles identified were further reviewed in full text to
examine their eligibility. In addition, four of the authors
independently reviewed the full articles to abstract
the relevant data required for the review. Thereafter,
a meeting to harmonise findings were done and pre-
sented in a report.

Data extraction and appraisal of the study
We extracted information from each study, including
author, study population, year of publication, coun-
try, socio-demographic characteristics, sample size,
response rate, gender proportion, age, and study time,
areas assessed, the validated instrument used and the
prevalence. The appraisal involved assessing the research
design, recruitment of respondents, inclusion and exclu-
sion criteria, reliability of outcome determination, statis-
tical analyses, ethical compliance, strengths, limitations,
and clinical implications of the articles.

Our review protocol was not registered on PROSPERO
because of the significant variation in the methodologies
of the articles used in the review. The results precluded
using a meta-analytic approach and made a narrative
review the most suitable for this work. In addition, we
did not use the Cochrane Collaboration GRADE method
to assess the quality of evidence of outcomes included in
this narrative review. Instead, we used the Strengthening
the Reporting of Observational studies in Epidemiology
(STROBE) 22 items checklist to gauge the quality of the
twelve articles included in this review. We qualitatively
validated the articles based on additional considerations
namely study design, sample sizes, sampling procedures,
response rates, statistical methods used, measures taken
by the authors to deal with bias and confounding factors
and ethical consideration.

Definition of healthcare worker (HCW)
For this narrative review, we adhered to the Centres for
Disease Control and Prevention (CDC) definition of
HCWs, which includes physicians, nurses, emergency
medical personnel, dental professionals and students,
medical and nursing students, laboratory technicians,
pharmacists, hospital volunteers, and administrative staff
[34].

Results
Search results
The search found twenty-three studies of interest. Full
texts of potentially relevant studies underwent eligibility
assessment, and twelve articles met the inclusion criteria
for this narrative review.

Page 4 of 16Oyat et al. BMC Psychology (2022) 10:284

Ta
bl

e
1

St
ud

y
ch

ar
ac

te
ris

tic
s

an
d

ou
tc

om
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m
ea

su
re

s/
n

A
ut

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un

tr
y

St
ud

si
gn

Sa
m

pl
in

g
Pr

oc
ed

ur
e/

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m

pl
e

Si
ze

(n
)

In
st

ru
m

en
t A

pp
lie

d
M

ai
n

ou
tc

om
e

m
ea

su
re

1
M

uz
ya

m
ba

e
t a

l.
[3

5]
U

ga
nd

a
Q

ua
lit

at
iv

e
st

ud
y

C
ro

ss
-s

ec
tio

na
l

O
nl

in
e

se
lf-

ad
m

in
is

te
re

d
qu

es
tio

n-
na

re
s

Ra
nd

om
s

el
ec

tio
n

n
=

5
0

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on

tli
ne

H
C

W
s,

m
al

Q
ua

lit
at

iv
e

O
nl

in
e

su
rv

ey
to

ol
s

D
ep

re
ss

io
n,

a
nx

ie
ty

a
nd

P
TS

D
Ri

sk
s:

lo
ng

w
or

ki
ng

h
ou

rs
, l

ac
k

of
e

qu
ip

–
m

en
t,

PP
Es

, T
es

in
g

ki
ts

, l
ac

s
le

ep
,

ex
ha

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tio

n,
h

ig
h

de
at

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s,

de
at

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of

lle
ag

ue
s,

hi
gh

ra
te

s
of

tr
an

sm
is

si
on

Co
pi

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s

tr
at

eg
ie

s:
Fa

m
ily

n
et

w
or

ks
,

co
m

m
un

ity

et
w

or
ks

, h
el

ps
fr

om
fa

m
ily

,
re

sp
on

si
bi

lit
y

to
s

oc
ie

ty
, a

ss
is

ta
nc

e
fro

co
m

m
un

ity
m

em
be

rs
, a

va
ila

bi
lit

y
of

si
st

fr
om

s
tr

an
ge

rs
a

nd
s

ym
bi

ot
ic

tu
re

o
f a

ss
is

ta
nc

e
in

c
om

m
un

ity

2
Sa

ga
on

T
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t a

l.
[3

9]
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al
i

Q
ua

nt
ita

tiv
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st
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C

ro
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-s
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tio
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l
N

on
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on
tli

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H

C
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in

vo
lv

ed
in

H
IV

N
on

-p
ro

ba
bi

lit
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sa
m

pl
in

n
=

1
35

(6
0.

m
al

e,
m

ea
n

ag
e

40
yr

s)
PH

Q
-9

, (
20

–2
7)

; G
A

D
-7

, (
0–

21
),

7
IS

I (
0–

28
)

Pr
ev

al
en

ce
: D

ep
re

ss
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7
1.

9%
, a

nx
ie

at
7

3.
5%

, a
nd

In
so

m
ni

a
at

7
7%

Ri
sk

fa
ct

or
s:

fe
m

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e,

la
ck

o
f P

PE
s,

an
d

la
ck

n
ur

se
s

21
.5

%
h

ad
s

ev
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de

pr
es

si
on

D
ep

re
s-

si
on

w
as

6
0%

m
or

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lik

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in
fe

m
al

es
th

m
al

3
G

eb
re

Ye
su

s
FA

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t a

l.
[3

6]
Et

hi
op

ia
Q

ua
nt

ita
tiv

e
st

ud
y

C
ro

ss
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tio

na
l,

Se
lf-

ad
m

in
is

te
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d
qu

es
tio

nn
ai

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s

Pr
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ab
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s

am
pl

in
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ub

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=

3
22

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es

po
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ra

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9

6.
5%

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al

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.9

PH
Q

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, P

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ce

: D
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2

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tr

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ve

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pr
ev

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of
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w
as

3
6%

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sk

fa
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s:

ag
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g
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de
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lo

in
co

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p
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of

in
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m
em

be
r o

f
a

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w

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fa

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cc

up
a-

tio
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M

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at

u
H

A
, e

t a
l.

[3
7]

Et
hi

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Q
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tiv
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ss

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s

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t.

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ic

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on
tli

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7

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, G

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, I

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d

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tr

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1

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5%

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sk

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ct

or
s:

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ar

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fr
on

tli
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w
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,
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po
su

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to

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D

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9

ca
se

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st

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m

in
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m

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, w

or
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sh
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en

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ith

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ng

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h

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rs

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ac

k
of

gi
st

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s

up
po

rt
s,

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&
p

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r o

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od

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io

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at

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kp
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A

ya
le

w
, e

t a
l.

[3
8]

Et
hi

op
ia

Q
ua

nt
ita

tiv
e

st
ud

y
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ro
ss

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ec

tio
na

l s
tu

dy
d

es
ig

n.
S

el
f-

ad
m

in
is

te
re

d
qu

es
tio

nn
ai

re
s

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ob

ab
ili

ty
s

am
pl

in
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ro

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&

N
on

–
fro

nt
lin

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H

C
W

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in

fo
ur

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ub

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H

os
pi

ta
ls

,
n
=

3
87

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es

po
ns

e
ra

te
9

1.
7%

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al

58
.7

%
, S

ou
th

er
n

Et
hi

op
ia

IE
S-

R
Pr

ev
al

en
ce

: P
TS

D
a

5
6.

8%
Si

gn
ifi

ca
nt

ri
sk

fa
ct

or
s

w
er

e
ag

e,
w

or
k-

in
g

en
vi

ro
nm

en
t,

pr
of

es
si

on
s,

fe
m

al
e,

ar
rie

d,
a

nd
n

ur
se

. I
n

pa
tie

nt
s,

w
or

ke
rs

,
em

er
ge

nc
y

w
or

ke
rs

, a
nd

IC
U

,
In

de
pe

nd
en

t p
re

di
ct

or
s

w
er

m
al

es
,

m
ar

rie
d

an
d

nu
rs

6
Je

m
al

K
, e

t a
l.

[4
0]

Et
hi

op
ia

Q
ua

nt
ita

tiv
e

st
ud

y
C

ro
ss

-s
ec

tio
na

l
Se

lf-
ad

m
in

is
te

re
d

Q
ue

st
io

nn
ai

re
s

Pr
ob

ab
ili

ty
s

am
pl

in
g.

F
ac

ili
ty

b
as

ed
s

tu
dy

n
=

4
17

, R
es

po
ns

e
ra

te
9

8.
6%

. N
or

Sh
oa

Z
on

e,
O

ro
m

iy
a

PH
Q

-9
, G

A
D

-7
, I

SI
, I

ES
-R

Pr
ev

al
en

ce
: D

ep
re

ss
io

n
at

1
6.

3%
, a

nx
ie

at
3

0.
7%

, I
ns

om
ni

a
at

1
5.

9%
, a

nd
S

tr
es

s
at

5
8%

Page 5 of 16Oyat et al. BMC Psychology (2022) 10:284

Ta
bl

e
1

(c
on

tin
ue

s/
n

A
ut

ho
rs

Co
un

tr
y

St
ud

y
de

si
gn

Sa
m

pl
in

g
Pr

oc
ed

ur
e/

Sa
m

pl
e

Si
ze

(n
)

In
st

ru
m

en
t A

pp
lie

d
M

ai
n

ou
tc

om
e

m
ea

su
re

7
C

he
ko

le
Y

A
.,

et
a

l.
[4

1]
Et

hi
op

ia
Q

ua
nt

ita
tiv

e
st

ud
y

C
ro

ss
-s

ec
tio

na
l

Se
lf-

ad
m

in
is

te
re

d
qu

es
tio

nn
ai

re
s

Pr
ob

ab
ili

ty
s

am
pl

in
g,

In
st

itu
tio

na
l H

C
Ps

n
=

2
44

re
sp

on
se

ra
te

1
00

%
, M

al
es

6
6%

PS
S-

10
PT

SD
P

re
va

le
nc

e
w

as
5

1.
6%

Ri
sk

fa
ct

or
s

w
er

e
ag

e,
a

nd
e

du
ca

tio
na

l
qu

al
ifi

ca
tio

ns
A

ge
a

nd
p

ro
fe

ss
io

n
w

er
e

in
de

pe
nd

en
t

pr
ed

ic
to

rs
o

f s
tr

es
s.

Fr
on

tli
ne

H
C

W
s

ha
d

a
st

ro
ng

s
ta

tis
tic

al
a

ss
oc

ia
tio

n
w

ith

st
re

ss
, n

ur
se

ar
m

ac
is

ts
, f

ro
nt

lin
es

,
an

d
m

as
te

r’s
d

eg
re

8
A

sn
ak

w
e

t a
l.

[4
3]

Et
hi

op
ia

Q
ua

nt
ita

tiv
e

st
ud

y
C

ro
ss

-s
ec

tio
na

l s
tu

dy
d

es
ig

n,
M

ul
tic

en
–

tr
e

se
lf-

ad
m

in
is

te
re

d
qu

es
tio

nn
ai

re
s

H
os

pi
ta

l w
or

ke
rs

Pr
ob

ab
ili

ty
s

am
pl

in
g,

n
=

3
96

re
sp

on
se

te
9

3.
6%

. M
al

es
6

9.
2%

fe
m

al
es

30
.8

%
N

or
th

w
es

t E
th

io
pi

IE
S-

R-
22

PT
SD

p
re

va
le

nc
e

w
as

5
5.

1%
Ri

sk
fa

ct
or

s
w

er
e

la
ck

o
f s

ta
nd

ar
d

PP
Es

,
ag

e
>

4
0,

m
ed

ic
al

il
ln

es
s,

fe
m

al
es

,
pe

rc
ei

ve
s

tig
m

a,
h

is
to

ry
o

f m
en

ta
l i

ll-
ne

ss
, p

oo
r s

oc
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Page 6 of 16Oyat et al. BMC Psychology (2022) 10:284

Study characteristics
The twelve articles comprised eleven quantitative and
one qualitative study. The common mental health con-
ditions assessed were depression, anxiety, perceived
stress, and post-traumatic stress disorder (PTSD). The
coping strategy, perceived health status, health dis-
tress (including burnout), insomnia, and perceived
stigma were also assessed [35, 36]. The total number
of respondents in these studies was 5,323. The quali-
tative study had fifty respondents [35], while the most
significant number of participants, 420 was recorded
in one of the quantitative studies from Ethiopia [37].
The questionnaire response rates varied between 90%-
100%, with most studies dominated by male respond-
ents at 51.9%-69.2% [38]. Nurses were the commonest
study population, followed by doctors, pharmacists,
and laboratory technicians, and no study involved
non-HCWs of facilities. Most papers utilized probabil-
ity sampling procedures, and four quantitative studies
used non-random sampling procedures limiting gen-
eralizability of their findings and increasing the risk of
selection bias. Eight studies were from Ethiopia, and
one was from Cameroon, Uganda, Mali, and Togo,
respectively (Table 1). Most studies were conducted in
urban tertiary public hospitals, university teaching hos-
pitals, and rural and urban general hospitals, including
primary care facilities operated by Non-Governmental
Organizations (NGOs) for example in Mali [39]. Several
validated tools assessed depression, anxiety, insomnia,
stress, and PTSD (Table 1).

Table 1 provides an overview of the studies selected
and validated instruments used to measure psychological
disorders.

Table 2 provides comparisons with studies conducted
outside of sub-Saharan Africa.

Table 3 provides information on studies showing the
classification of psychological outcomes.

Table 4 are studies showing risk factors associated with
psychological disorders.

Table 5 are studies that identified protective factors for
psychological disorders.

Risks of bias and confounding factors
Most articles selected were cross-sectional studies that
employed probability sampling procedures (Table 1).
Cross-sectional study design minimized selection
biases, but many used structured questionnaires, includ-
ing online self-administered questionnaires, which
increased bias due to social desirability. It was not clear
how confounding variables were controlled in five papers
reviewed [38–40, 43, 45] leading to excessive and perhaps
inappropriate determination of associations.

Socio‑demographic factors
Age
In this review, the mean age of the respondents ranged
between 23 and 35 years, and predominantly males.
Age was associated with anxiety, and stress symptoms
in 6(50%) of all the studies reviewed [35, 37, 40–42, 44].
An age of over 40 years was associated with moderate
to severe symptoms of PTSD. Two studies concluded
that respondents aged over 40 years were more likely to
develop PTSD symptoms than their younger counter-
parts [37, 41].

Gender
Female gender was significantly associated with depres-
sion, anxiety, and stress symptoms among HCWs in
seven studies reviewed [36–38, 41–43]. Many studies
found that being female, married, and a nurse were inde-
pendent predictors of stress symptoms. Moreover, sex,
age, marital status, type of profession, and working envi-
ronment were significant factors for PTSD symptoms [37,
41]. However, one study in Ethiopia found that the odds
of depression were twice higher among male healthcare
providers than among female healthcare providers [35].

Psychological impact on healthcare workers
Most studies reviewed directly assessed the prevalence
of depression, anxiety, stress, insomnia, and PTSD in
HCWs. Common causes of anxiety, fear, or psychologi-
cal distress that health professionals reported were: lack
of access to PPEs and other equipment, being exposed
to COVID-19 at work and taking the infection home to
their families, uncertainties that their organization will
support/take care of their personal and family needs
if they got infection, long working hours, death of col-
leagues, lack of social support, stigmatization, high rates
of transmission and poor income [35–45]. However,
the prevalence of mental health symptoms exhibited
great variations for example depressive symptoms were
examined in nine studies [35–37, 39, 43–46], and varied
between 16.3% and 71.9% among HCWs [38, 39].

In addition, nine other studies reported high preva-
lence of anxiety symptoms among HCWs [35–37, 40,
43–47] which varied between 21.9% and 73.5% [36, 39].
Five studies investigated HCWs’ perceived stress during
the pandemic; 15.5%-63.7% of HCWs reported high lev-
els of work-related stress [35–37, 43, 45]. Three studies
reported 12.4–77% of HCWs experienced sleep distur-
bances during the COVID-19 pandemic [37, 39, 40].

Post-traumatic stress disorder (PTSD) was in three
studies [38, 41, 42], and the prevalence of PTSD-like
symptoms varied between 51.6 and 56.8% in HCWs
[38, 41]. A qualitative study from Uganda reported high
symptoms of depression, anxiety, and PTSD among

Page 7 of 16Oyat et al. BMC Psychology (2022) 10:284

HCWs [35]. Additionally, factors that increased the risk
of PTSD symptoms were for example, working in emer-
gency units and being frontline workers. Furthermore,
many studies found that frontline HCWs had increased
symptoms of mental disorders and being a frontline
worker was an independent risk factor for depression,
anxiety, and PTSD [36–46].

Risk factors associated with adverse mental health
outcomes
The qualitative study from Uganda reported the fac-
tors associated with mental disorder symptoms among
HCWs. These were long working hours, lack of equip-
ment (PPEs, testing kits), lack of sleep, exhaustion, high
death rates, death of colleagues, and a high COVID-19
transmission rate among HCWs [35]. Lack of equip-
ment (PPEs, ventilators, and testing kits), overworking,
and lack of logistic support were in Ethiopian studies
[36–42, 45]. Most studies identified several risk factors
for adverse mental health outcomes among respondents
for example those with medical and mental illnesses,
contacts with confirmed COVID-19 patients, and poor
social support which were significantly associated with
depression [42, 43]. Other factors were females, nurses,
married, frontline workers, ICU, emergency units, living
alone, and lack of social support [35, 37–45]. Too, par-
ticipants’ families with chronic illnesses, had contacts
with confirmed COVID-19 cases, and poor social sup-
port were significantly associated with anxiety. Other risk
factors associated with anxiety include exhaustion, long
working hours, frontline workers, emergencies, nurses,
pharmacists, laboratory technicians, married, older,
younger, living alone, being female, working at general
and referral hospitals, and perceived stigma. In addi-
tion, participants’ families with chronic illnesses, those
who had contacts with confirmed COVID-19 cases, and
those with poor social support were predictors of stress
during the COVID-19 pandemic [37, 38, 40–43, 45].
Other stress symptoms include having a medical illness,
a mental illness, being a frontline worker, married, nurse,
female, pharmacist, laboratory technician, physician,
older age, lack of standardized PPE supply, low incomes,
and living with a family [36, 37, 40–45]. Healthcare pro-
viders with low monthly incomes were significantly more
likely to develop stress than those with high monthly
incomes [38]. In addition, participants living alone, liv-
ing with a family, and being married were associated
with symptoms of psychological disorders among HCWs
[36–38, 45]. Overall, the risk factors for adverse psycho-
logical impacts are categorized in three thematic areas (i)
occupational, (ii) psychosocial, and (iii) environmental
aspects.

Occupational factors
Most studies showed that frontline HCWs, nurses, doc-
tors, pharmacists, and laboratory technicians had signifi-
cantly higher levels of mental health risks compared to
non-frontline HCWs [35–38, 40, 42, 43, 45]. They experi-
enced higher frequency of insomnia, anxiety, depression,
and somatization than non-frontline medical HCWs. In
contrast, Mali [39] and Cameroon [46] studies found a
higher prevalence of depression, anxiety, and PTSD in
non-frontline HCWs [39, 46]. However, among HCWs,
physicians were 20% less likely to develop mental health
disorders than nurses, pharmacists, and laboratory tech-
nicians [39]. In addition, healthcare workers with low
monthly incomes had higher symptoms of depression,
anxiety, stress, and insomnia [37].

Healthcare groups
Five studies found that being a nurse was associated with
worse mental disorders than doctors [36, 37, 40, 44, 45].

Frontline staff with direct contact with COVID‑19
Most papers in the review found that being in a “front-
line” position or having direct contact with COVID-19
patients was associated with higher level of psychological
distress [35–38, 40, 42, 43, 45]. In addition, studies found
that contact with COVID-19 patients was independently
associated with an increased risk of sleep disturbances
[40, 46]. Moreover, HCWs who had contact with con-
firmed COVID-19 cases were more likely to develop
depression, anxiety, and stress symptoms than those who
had no contact with COVID-19 patients [36–38, 43, 45].

Lack of personal protective equipment (PPEs)
Most studies reported that the lack of PPEs was associ-
ated with higher symptoms of depression, anxiety, stress,
and insomnia, while its availability was associated with
fewer mental disorder symptoms [35–46]. In Mali, work-
ers from centres that provided facemasks were 51% less
likely to suffer from depression, 62% less likely to develop
anxiety, and 45% less likely to develop insomnia [39]. In
Ethiopia, the odds of developing post-traumatic stress
disorder were much higher among HCWs who did not
receive standardized PPEs supplies than those who had
[38, 41, 42]. In Uganda, the lack of PPEs was associated
with depression, anxiety, and PTSD [35].

Heavy workload
Longer working hours, increased work intensity,
increased patient load, and exhaustion were risk factors
in Ugandan [35] and Ethiopian studies [36].

Page 8 of 16Oyat et al. BMC Psychology (2022) 10:284

Psychosocial factors: perceived stigma and fear of infection
The fear of infection was in the qualitative study from
Uganda [35], one quantitative study from Cameroon [47]

and seven cross-sectional studies from Ethiopia [36–38,
41–44]. Poor social support was associated with PTSD
symptoms, depression, anxiety, and stress [35–38, 42,

Table 2 Comparisons of the prevalence of mental health disorders among HCWs in different regions

HCWs Healthcare workers;

PTSD posttraumatic stress disorder

s/no Authors/Country/Regions Study design Population Period Outcome

1 Chen J et al. Africa Systematic Review/Meta-
analysis

Frontline/General/
HCWs/4,847

Dec.2019–April 2020 Anxiety 51%, depression 45%,
and insomnia 28%

2 Pappa S et al. China Systematic Review/Meta-
analysis

HCWs, 33,062 17 April 2020 Anxiety 23.2%, depression
22.8%, and
Insomnia 38.9%

3 Li Y, et al. China Systematic Review/Meta
analysis

HCWs 33,062 17 April 2020 Anxiety 22.1%, depression
21.7%, and
PTSD 21.5%

4 Basreeqa SB et al. China Systematic Review/Meta
analysis

General Population Front-
line/General HCWs. 62,382

First six months of 2020 Anxiety 48.1%, depression
26.9%, and
Stress 48.1%

5 Preti E et al., Asia, Middle
East, Europe, USA

Rapid Review HCWs March 2020 Anxiety 45%, depression
27.5–50.7%,
Stress 18.1–80.1%, Insomnia
34–36%, and
PTSD 11–73.4%

6 Lai J. China Cross-sectional HCWs First six months of 2020 Anxiety 44.6%, depression
50.4%,
distress 71.5%, and insomnia
34%

7 Tan BYQ. Singapore Cross-sectional General population /HCWs First six months of 2020 Anxiety 14.5%, depres-
sion8.9%,
Stress 6.6%, and PTSD 7.7%

8 Consolo U et al. Italy Cross-sectional HCWs First six months of 2020 Anxiety 46.4%, depression
70.2%, and
stress 42.4%

9 Gilleen J et al. UK Cross-sectional HCWS First six months of 2020 Anxiety 33%, Depression 28%,
and PTSD 15%

10 Shacther A, et al. NY, USA Cross-sectional HCWs First six months of 2020 Anxiety 33%, depression 48%,
and
stress 57%

11 Urooj U, et al. Pakistan Cross-sectional HCWs First six months of 2020 Anxiety 86%, depression 58%,
and stress 28.8%

12 Wilson W, et al. India Cross-sectional HCWs First six months of 2020 Anxiety 17.7%, depression
11.6%, and stress 3.7%

13 Elhadi M, et al. Libya Cross-sectional HCWs Early 2022 Anxiety 46.7%, and depres-
sion 56.3%

Table 3 Classification of studies according to psychological outcomes

Measures’ descriptions: Depression: PHQ-9 Patient Health Questionnaire. Anxiety: GAD-7 Generalised Anxiety Disorder Questionnaire, Depression & Anxiety: DASS-21
Depression, Anxiety and Stress Scale, Sleep: ISI Insomnia Severity Index; IES-R Impact of Event Scale; HADS Hospital Anxiety and Depression scale, PSS-10 Perceived
Stress Scale; PMS-9 Premenstrual Syndrome Scale; OSS Oslo 3 items for social support

Psychological Outcome Studies Measurement tools Prevalence

Anxiety [34–36, 38, 39, 42–45] GAD-7, DASS-21, HADS 21.9–73.5%

Depression [34–36, 38, 39, 42–45] PHQ-9, GAD-7, HADS 16.3–71.9%

PTSD [34, 37, 40, 41] IES-R, PSS-10 51.6–56.8%

Stress [35, 36, 42–44] IES-R, OSS, PSS-10 15.5–63.7%

Insomnia [35, 36, 38, 39] ISI 12.4–77%

General psychological disorders [35] PSS, PHQ-9 36%

Page 9 of 16Oyat et al. BMC Psychology (2022) 10:284

43]. Two studies reported that HCWs with perceived
stigmatization were more likely to suffer from depres-
sion, anxiety, stress, and PTSD [37, 42].

family concerns
This came up as one of the main risk factors of stress
in almost all studies, especially among those HCWs in
direct contact with confirmed COVID-19 cases [35–38,
40–45]. A family member suffering from COVID-19 was

associated with poor mental health outcomes in HCWs
[36, 37].

Protective psychosocial factors
Two studies suggest a reduction of perceived stigma
can be achieved by sensitization of communities about
COVID-19 [37, 42], and four studies recommend solid
social support [36, 37, 42, 43].

Table 4 Studies showing risk factors associated with psychological disorders

*positive association; N/A No association

Variables PTSD Anxiety Depression Insomnia Stress General
psychological
disorders

Age [38, 41, 42] * [36] * N/A N/A [36] * [36] *

Female Gender [38, 42]* [36, 39, 43–45] * [36, 39, 43–45] * [37, 39] * [36, 43] * N/A

Marital status [38] * [37] * [37] * [37] * N/A N/A

Education [41] * N/A N/A N/A N/A N/A

Income N/A [36] * [36] * [36] * [36] * N/A

Physicians N/A [41, 42] * [37, 43, 44] * [37, 43–45] * [36, 37] * N/A

Nurses [38, 41] * [35, 37, 44, 45] * [35, 37, 44, 45] * [36, 37] * [35–37] * N/A

Pharmacists [38, 41] * [36, 37, 39, 44, 45] * [36, 37, 39, 44, 45] * [36, 37] * [36, 37] * N/A

Lab. Tech [38, 41] * [36, 37, 39, 44, 45] * [36, 37, 39, 44, 45] * [36, 37] * [35–37, 45] * N/A

Frontline workers [38, 41, 42] * [35–39, 41–45] * [35–39, 41–45] * [36, 37] * [35–37, 45] * N/A

Stigma [42] * [37] * [37] * [37] * [37] * [37] *

Medical illness [42] * [37, 43, 44] ** [37, 43, 44] * [37] * [37, 43] * N/A

Mental Illness [42] * [43, 44] * [43, 44] * N/A [43] * N/A

Lack of PPEs [38, 41, 42] * [35–39, 41–45] * [35–39, 41–45] * [35–37] * [35–37] * N/A

Contact with COVID-19 cases [38, 41, 42] * [35–37] * [35–37] * [35–37] * [35–37, 43] * N/A

Poor Social support [42] * [37, 43] * [37, 43] * [37, 43] * [43] * N/A

Living Alone N/A [45] * [45] * [45] * N/A [45]

Living with a family N/A [36] * [36] * N/A [36] * N/A

Infected family member N/A [36, 37] * [36, 37] * [36, 37] * [36, 37] * N/A

Table 5 Studies that identify protective factors for psychological disorders

PTSD posttraumatic stress disorder

Variables PTSD Anxiety Depression Insomnia Stress

Availability of PPEs [35, 38, 41, 42] [35–37, 42, 43] [35–37, 42, 43] [35–37, 42, 43] [35–37, 42, 43]

Experience [35, 42] [37, 42, 45] [37, 42, 45] [37, 42, 45] [37, 42, 45]

Training/orientation [35, 42] [37, 42, 45] [37, 42, 45] [37, 42, 45] [37, 42, 45]

Safety of Family [35] [35, 36] [35, 36] [35, 36] [35, 36]

Availability of testing kits [35] [35] [35] [35] [35]

Work shifts arrangement [35] [37] [37] [37] [37]

organizational support [35] [37] [37] [37] [37]

Online Psychological support [35, 42] [37, 42] [37, 42] [37, 42] [37, 42]

Better income [35] [36] [36] [36]

Strong Social Support [35, 42] [35–37, 42, 43] [35–37, 42, 43] [35–37, 42, 43] [35–37, 42, 43]

Community Support [35, 42] [35, 43] [35, 43] [35, 43] [35, 43]

Page 10 of 16Oyat et al. BMC Psychology (2022) 10:284

Safety of family
Family safety had the most significant impact in reduc-
ing stress. Safety from COVID-19 infection and financial
protection of families were essential coping strategies for
HCWs [35, 36].

Underlying illnesses
We found three studies that reported an underlying med-
ical and mental illness as an independent risk factor for
poor psychological outcomes [42, 43, 45].

Protective factors against adverse mental health outcomes
The review identified protective factors to adverse mental
health outcomes during COVID-19. The qualitative study
from Uganda and four quantitative cross-sectional stud-
ies from Ethiopia identified some protective factors [35,
38, 41, 42, 45]. The protective factors are grouped under
three thematic areas (i) occupational, (ii) psychosocial,
and (iii) environmental aspects.

The qualitative study identified many social coping
strategies among respondents, including family net-
works, community networks, help from family, respon-
sibility to society, assistance from community members,
availability of assistance from strangers, and the symbi-
otic nature of assistance in the community [35].

Protective occupational factors

Experience Studies suggest that physicians suffered
fewer mental health disorders partly because of their
experience with previous epidemics [37, 42, 45].

Trainings Some necessary coping measures include
good hospital guidance and ongoing training of frontline
HCWs [37, 42, 45].

Adequate supply of PPEs As mentioned above, PPE was
a protective factor when adequate and a risk factor for
poor mental health outcomes when deemed inadequate
[35–37, 42, 43].

Discussion
The COVID-19 pandemic has been an ongoing global
public health emergency that has burdened healthcare
workers’ physical and mental well-being (HCWs) [1, 5].
Our review confirms the enormous magnitude of men-
tal health impact of COVID-19 on healthcare workers in
sub-Saharan Africa, and it is widespread, with significant
levels of depression, anxiety, distress, and insomnia; espe-
cially those working directly with COVID-19 patients at
particular risk [34–37, 39–45]. Out of the twelve articles
reviewed, eight studies (66%) came from Ethiopia, and
this has implications on the results (Table 1). This finding

indicates few research published to date on the psycho-
logical impact of the pandemic on the mental health
of HCWs in sub-Saharan Africa; a subregion that the
COVID-19 pandemic has severely impacted.

Overview of the study sites
Studies in this review were conducted predominantly in
hospital settings. We found only one study relating to
primary healthcare workers or facilities [38]. This finding
is of concern, as there is increasing evidence that many
non-frontline HCWs continue to suffer psychological
symptoms long after the conclusion of infectious dis-
ease epidemics [7, 8]. In addition, a significant mortality
due to COVID-19 was due to excess morbidity, some of
which were from primary care facilities. Given that this
study is the first narrative review in sub-Saharan Africa,
it would be helpful to briefly compare our findings with
some published reviews and surveys from other regions
(Table 2).

High prevalence of psychological disorders
among participants
Investigators in this review found 16.3–71.9% HCWs
with depressive symptoms, 21.9–73.5% had anxiety
symptoms, 15.5–63.7% experienced work-related stress
symptoms, 12.4–77% experienced sleep disturbances,
and 51.6–56.8% PTSD symptoms [35–45]. This high
prevalence of mental health symptoms among HCWs in
our review is consistent with previous reviews conducted
early in the pandemic in sub-Saharan Africa [31], Asia
[17, 18, 26, 28], USA & Europe [15, 16], and supported by
a batch of cross-sectional studies globally [11–14, 19, 27,
30]. We found mixed results with significant variations
within and among regions and countries, as depicted in
Tables 1 and 2.

Risk factors of psychological disorders among participants
Studies established that HCWs responding to the
COVID-19 pandemic in sub-Saharan Africa were
exposed to long working hours, overworking, exhaus-
tion, high risk of infection, and shortage of personal pro-
tective equipment (Tables 3 and 4). In addition, HCWs
had deep fear, were anxious and stressed with the high
transmission rate of the virus among themselves, high
death rates among themselves and their patients, and
lived under constant fear of infecting themselves and
their families with obvious consequences [35–45]. Some
HCWs were deeply worried about the lack of standard-
ized PPEs, known treatments and vaccines to protect
against the virus. Many health workers had financial
problems, lacked support from families and employers
if they contracted the virus [34–37, 39–42, 44]. An addi-
tional source of fear and anxiety was the perceived stigma

Page 11 of 16Oyat et al. BMC Psychology (2022) 10:284

attached to being infected with COVID-19 by the pub-
lic [36, 41]. Studies found that HCWs, especially those
working in emergency, intensive care units, infectious
disease wards, pharmacies, and laboratories, were at
higher risk of developing adverse mental health impacts
compared to others [34–37, 39–44]. This is supported
by previous reviews [15–18, 26, 28] and cross-sectional
studies [10–14, 20, 21, 23, 25, 30]. However, findings
were inconsistent on the impact of COVID-19 on front-
line health workers, with ten studies [35–37, 39–42, 44,
45] suggesting they are at higher risk than peers and two
studies showing no significant difference in psychological
disorders relating to the departments [38, 43].

The Mali’s study was conducted exclusively in primary
care facilities among HCWs not involved in treating
COVID-19 cases but still registered a very high preva-
lence of depression 71.9%, anxiety 73.6%, and insomnia
77.0% [39]. In contrast, two studies conducted among
HCWs at COVID-19 treatment facilities in Ethiopia
[36, 38] registered much lower prevalence of depres-
sion 20.2%, anxiety 21.0%, and insomnia12.4% [36], and
16.3%, 30.7% and 15.9% respectively, in the second study
[38]. These findings show that not only frontline HCWs
experienced mental health disorders during this pan-
demic but highlight the need for direct interventions for
all HCWs regardless of occupation or workstation dur-
ing this and future pandemics. The significant disparity
in the studies could be due to structural, occupational,
and environmental issues for example challenges faced by
Mali’s healthcare systems, characterized by acute equip-
ment shortages, lack of PPEs, human resources, lack of
trained and experienced HCWs, ongoing nationwide
insecurity, and terrorism compared to Ethiopia. There-
fore, local context needs to be considered as contributing
factor to mental health disorders among HCWs.

Regional variations of psychological disorders
Tan et al. found a higher prevalence of anxiety among
non-medical HCWs in Singapore [27]. As previously
noted, the prevalence of poor psychological outcomes
varied between countries. Compared to sub-Saharan
Africa and China, data from India [23] and Singapore
[27] revealed an overall lower prevalence of anxiety and
depression than similar cross-sectional data from sub-
Saharan Africa [35–45] and China [9, 25, 30]. This find-
ing suggests that different contexts and cultures may
reveal different psychological findings and that, it is pos-
sible that being at different countries’ outbreak curve may
play a part, as there is evidence that it is influential.

Tan et al. suggests that medical HCWs in Singapore
had experienced a SARS outbreak and thus were well
prepared for COVID-19 psychologically and infection
control measures [27]. What can be deduced is that

context and cultural factors play a role, not just the cadre
or role of healthcare workers [16]. It also highlights the
importance of reviewing evidence regularly as more data
emerge from other countries.

One hospital in Ethiopia found that the thought of
resignation was associated with higher chances of men-
tal health disorders and that pharmacists and laboratory
technicians who did not receive prior training exhibited
higher symptoms of mental health disorders compared to
others [36]. Work shift arrangement, considering a dan-
gerous atmosphere presented by working in COVID-19
wards, was one which exacerbated or relieved mental
health symptoms among HCWs, with shorter exposure
periods being most beneficial [36]. Meanwhile, studies
found that financial worries caused by severe lockdowns
and erratic payment of salaries and allowances were also
major stressors [35]. This finding is like studies in Paki-
stan [13] and China [30, 32].

In this review, HCWs who had contact with confirmed
COVID-19 patients were more affected by depression,
anxiety, and stress than their counterparts who had
not [35–37, 40, 41, 43, 45]. This finding is like previous
reviews [15–18, 26, 28, 31] and cross-sectional studies
[9–14, 21, 23–25, 27, 30], which reported higher depres-
sion, anxiety, and psychological symptoms of distress in
HCWs who were in direct contact with confirmed or sus-
pected COVID-19 patients.

A study in Pakistan showed that 80% of participants
expected the provision of PPE from authority [13], and
86% were anxious. Some respondents alluded to forced
deployment, while in Mali, 73.3% were anxious, with
the majority worrying about the shortage of nurses [39].
Therefore, prospects of being deployed at a workstation
where one had not been trained or oriented contributed
to fear among health workers. In the sub-Saharan African
context, this scenario can best be represented in HCWs
involved in internship who must endure hard work dur-
ing their training. Tan et al. found that junior doctors
were more stressed than nurses in Singapore [27].

Socio‑demographic characteristics
Nearly all studies in our review suggest that socio-demo-
graphic variables for example age, gender, marital status,
and living alone or with families contribute to the high
mental disorder symptoms [35–37, 39–44]. We, the
authors suggest that these observations are handled cau-
tiously as several investigators of these reviewed articles
did not entirely control the influence of confounding
variables. An alternative explanation for this study’s find-
ings may be the more significant risks of frontline expo-
sure amongst women and junior HCWs, predominantly
employed in lower-status roles, many of whom lacked
experience and appropriate training within healthcare

Page 12 of 16Oyat et al. BMC Psychology (2022) 10:284

system globally. It is also important to note that respond-
ents to all studies, when disaggregated by gender, and
age, were predominantly younger or female, which may
have impacted the outcomes of these findings [16]. In
addition, the consistently higher mortality rates, and risk
of severe COVID-19 disease amongst men would suggest
that the complete picture regarding gender and men-
tal health during this pandemic is still incomplete [16].
Moreover, in several studies, both younger and older age
groups were equally affected by mental health symptoms
but for different reasons. Cai et al. [32] in a Chinese study
on HCWs for example observed that irrespective of age,
colleagues’ safety, self and families’ safety, the lack of
treatment for COVID-19 was a factor that induced stress
in HCWs. Similarly, in our review, the lack of PPEs, high
infection transmission rates, high death rates among
HCWs, and the fear of infecting their families were the
factors that induced stress in all HCWs [34–37, 39–45].

We, the authors propose that paying close attention to
concerns of HCWs by employers would greatly relieve
some stressors and contribute to increased mental well-
being of participants. Compared with physicians, our
review showed that nurses were more likely to suffer
from depression, anxiety, insomnia, PTSD, and stress [35,
37, 39–41, 44, 45]. Workloads and night shifts in health-
care facilities, as well as contacts with risky patients,
enhanced nurses’ mental distress risks [15–18, 26–28]. In
addition, nursing staff have more extended physical con-
tacts and closer interactions with patients than other pro-
fessionals, providing round-the-clock care required by
patients with COVID-19 and thus the increased risk [15].
On the one hand, we posit that most senior physicians
are experienced and always keep well-informed with
emerging medical emergencies. The majority become
aware of emerging epidemic early and actively protect
themselves from infections through regular scientific lit-
erature updates compared to their junior counterparts.
Senior physicians also spend less time in emergency
wards unless there is a need to conduct specific proce-
dures which cannot be undertaken by senior housemen
or general medical officers. Cai et al. [32] concluded that
it is essential to have a high level of training and profes-
sional experience for healthcare workers engaging in
public health emergencies, especially for the new staff. As
a result, these findings highlight the importance of focus-
ing on all the frontline HCWs sacrificing to contain the
COVID-19 pandemic.

Regular monitoring of high‑risk groups
There is a need to continue monitoring the high-at-risk
groups, including nursing staff, interns, support staff,
and all deployed in emergency wards. These high-at-risk
groups should be encouraged to undertake screening,

treatment, and vaccination to avoid the medium and
long-term consequences of such epidemics [15, 16, 35,
37, 40, 44].

Social support and coping mechanisms
The effect of social support and coping measures is in the
qualitative study [34] and three other quantitative stud-
ies [36, 41, 42] which concluded that respondents with
good social support were less likely to suffer from severe
depression, anxiety, work-related stress, and PTSD. The
qualitative study identified several coping measures,
including community and organizational support, family,
and community networks, help from family, responsibil-
ity to society, and assistance from community members
and strangers, including the symbiotic nature of assis-
tance in the community [35]. Other measures include
providing accommodation and food to employees [35].

Interestingly, no study examined the association of
resilience and self-efficacy with sleep quality, degrees of
anxiety, depression, PTSD, and stress. However, a Chi-
nese study by Cai et al. [32] suggests that the social sup-
port given to HCWs causes a reduction in anxiety and
stress levels and increases their self-efficacy. In diver-
gence, Xiao et al. [46] found no relationship between
social support and sleep quality.

Only two studies in our review examined the effects of
stigma on the mental health of HCWs [36, 41] and found
that HCWs with perceived stigma were more likely to
be depressed, anxious, stressed, and prone to poor sleep
quality [36, 41]. We, the authors suggest that better com-
munity sensitization by creating public awareness involv-
ing appropriate local community structures and networks
are essential. The broader community in sub-Saharan
Africa may have suffered severely from infodemics with
severe consequences on their mental health, especially
during the difficult lockdowns. In addition, removing dis-
crimination/inequalities at the workplace based on race
and other social standings have a powerful influence on
the mental health outcomes of HCWs. Also, because
emotional exhaustion is long associated with depression,
anxiety, and sleep disturbances, none of the studies in our
review examined burnout as an essential component of
mental health disorders in HCWs in sub-Saharan Africa.

Protective and coping measures
In this review we have provided evidence about per-
sonal, occupational, and environmental factors that were
important protective and coping measures against psy-
chological disorders. Based on these factors we suggest
some protective and coping measures which can help to
reduce the negative effects of the pandemic on mental
health of HCWs in sub-Saharan Africa. Organizations
and healthcare managers need to be aware that primary

Page 13 of 16Oyat et al. BMC Psychology (2022) 10:284

prevention is key to any successful interventions to con-
tain and control any epidemic. This should take the form
of planned regular training, orientation and continuing
medical education grounded on proven infection con-
trol measures. These measures need to be backed up by
timely provision of protective equipment, drugs, test-
ing facilities, vaccines, isolation facilities, clinical and
mental health support, and personal welfare of HCWs
[35–37, 42, 45]. The effect of community and organiza-
tional support and coping measures was shown by the
qualitative study [35] and five other quantitative stud-
ies [36, 37, 41–43] indicating that respondents who had
good social and organizational support were less likely
to suffer from severe depression, anxiety, work related
stress and PTSD. Prior experience with comparable pan-
demics and training are suggested as beneficial coping
strategies for healthcare workers during this pandemic
but also local social structural and geopolitical condi-
tions appear to determine the pattern and evolution of
mental health symptoms among HCWs [14, 15, 31, 32,
47]. In our case the high prevalence of all mental health
symptoms in non-frontline primary health care facili-
ties in Mali [39] which was already plagued with insta-
bility and weak healthcare systems prior to the pandemic
is a case in point. Results are particularly consistent in
showing that provision of PPEs, testing kits, orientation
training of workers, work shift arrangements, provision
of online counselling, provision of food and accommo-
dation and prompt payment of allowances by employers
were important protective measures [35–39, 41–47]. The
feeling of being protected is associated with higher work
motivation with implication for staff turnover [35, 38, 43,
45]. Hence, physical protective materials [14], together
with frequent provision of information, should be the
cornerstone of any interventions to prevent deterioration
in mental health of HCWs (Table 5). Finally, provision of
rest rooms, online consultation with psychologists/psy-
chiatrists, protection from financial hardships, access to
social amenities and religious activities are some impor-
tant coping measures [35, 36, 38, 42, 45]. In this era of
digital health care with plentiful internet and smart-
phones, organization can conduct online trainings,
online mental health education, online psychological
counselling services, and online psychological self-help
intervention tailored to the needs of their HCWs [35, 37,
42]. In addition, it is essential to understand and address
the sources of anxiety among healthcare professionals
during this COVID-19 pandemic, as this has been one
of the most experienced mental health symptoms [48].
Adequate protective equipment provided by health facili-
ties is one of the most important motivational factors for
encouraging continuation of work in future outbreaks.
Furthermore, availability of strict infection control

guidelines, specialized equipment, recognition of their
efforts by facility management, government, and reduc-
tion in reported cases of COVID-19 provide psychologi-
cal benefits [15, 32]. Finally, we call upon Governments
(the largest employers of HCWs) in sub-Saharan Africa
to do what it takes to improve investments in the mental
health of HCWs and plan proactively in anticipation of
managing infectious disease epidemics, including other
expected and unexpected disasters.

Future research direction
There was no study that examined the association of
resilience and self-efficacy with sleep quality, degrees of
anxiety, depression, PTSD, and stress. Although emo-
tional exhaustion has long been associated with depres-
sion, anxiety, and sleep disturbances, no study in our
review examined burnout as an important component of
mental health disorders in HCWs in sub-Saharan Africa.
The impacts of infodemics, stringent lockdown meas-
ures, discrimination/inequalities at workplaces based on
race, and other social standings on mental health out-
comes of HCWs need to be investigated.

Future studies are needed on the above including other
critical areas like suicidality, suicidal ideations, and sub-
stance abuse during the COVID-19 pandemic. In addi-
tion, there is a significant variation of related literature
calling for more rigorous research in future. More sys-
tematic studies will be required to clarify the full impact
of the pandemic so that meaningful interventions can be
planned and executed at institutional and national levels
in the Sub-Saharan Africa.

Limitations of this study
There are some limitations to this study. First, most of the
studies are from one country, limiting the generalizability
of the results to the whole African continent. Second, all
the studies were cross-sectional and only looked at asso-
ciations and correlations. There is a need for prospec-
tive or retrospective cohort or case–control studies on
this subject matter. Longitudinal research studies on the
prevalence of mental disorders in the COVID-19 pan-
demic in the sub-Saharan Africa are urgently required.
Third, most studies reviewed did not adequately examine
protective factors or coping measures of the health work-
ers in their settings. In addition, most studies did not pay
strict attention to confounding variables which could
have led to inappropriate results and conclusions. Fourth,
most sample sizes were small and unlikely representative
of the population and yet larger sample sizes would bet-
ter identify the extent of mental health problems among
health workers in the region. Fifth, depression, anxiety,
and stress were assessed solely through self-adminis-
tered questionnaires rather than face-to-face psychiatric

Page 14 of 16Oyat et al. BMC Psychology (2022) 10:284

interviews. Sixth, these studies employed various instru-
ments and different cut-off thresholds to assess severity.
Notably, the magnitude and severity of reported men-
tal health outcomes may vary based on the validity and
sensitivity of the measurement tools. Seventh, there was
no mention of mental baseline information among the
studied population and therefore it was unknown if the
studied population had pre-existing mental health ill-
nesses that decompensated during the pandemic cri-
sis. Eight, investigators did not give much attention to
stigma, burnout, resilience, and self-efficacy among study
participants.

Furthermore, our review did not employ systematic
reviews or meta-analyses methods for the informa-
tion generated. This narrative review paper precluded
deeper insight into the quality of reviewed articles for
this paper. Still, our observation was that investigators
did not consider the strict lockdown measures, quaran-
tine, and isolation imposed by many countries in sub-
Saharan Africa as possible risk factors for mental health
disorders among HCWs.

Conclusion
Based on the articles reviewed, the prevalence of depres-
sion, anxiety, insomnia, and PTSD in HCWs in the sub-
Saharan Africa during the COVID-19 pandemic is high.
We implore health authorities to consider setting up per-
manent multidisciplinary mental health teams at regional
and national levels to deal with mental health issues and
provide psychological support to patients and HCWs,
always supported with sufficient budgetary allocations.

Long-term surveillance is essential to keep track of
insidiously rising mental health crises among commu-
nity members. There is a significant variation of related
literature thus calling for more rigorous research in
the future. More systematic studies will be needed to
clarify the full impact of the pandemic so that meaning-
ful interventions can be planned better and executed at
institutional and national levels in sub-Saharan Africa.

Abbreviations
COVID-19: Coronavirus disease 2019; HCWs: Healthcare workers.; MH: Mental
health; PHE: Public health emergency; PPE: Personal protective equipment;
WHO: World Health Organisation.

Acknowledgements
We thank Uganda Medical Association Acholi-branch members for the finan-
cial assistance which enabled the team to conduct this study successfully.

Author contributions
FWDO, JA, JNO, ENI and DLK searched and screened studies and extracted
data from selected articles. FWDO wrote the first draft of the manuscript, and
all authors reviewed and edited the final draft. All authors approved the final
version of the manuscript.

Funding
N/A.

Availability of data and materials
Datasets analysed in the current study are available from the corresponding
author at a reasonable request.

Declarations

Ethics approval and consent to participate
Not applicable.

Consent for publication
Not applicable.

Competing interests
All authors declare no conflict of interest.

Author details
1 Uganda Medical Association (UMA), UMA-Acholi Branch, Gulu City, Uganda.
2 Moroto Regional Referral Hospital, Moroto, Uganda. 3 St. Joseph’s Hospital,
Kitgum District, Uganda. 4 ICAP at Columbia University, Freetown, Sierra Leone.
5 Rhites-N, Acholi, Gulu City, Uganda. 6 Faculty of Medicine, Department of Sur-
gery, Gulu University, P.O. Box 166, Gulu City, Uganda. 7 Harvard University,
Cambridge, USA.

Received: 3 September 2022 Accepted: 22 November 2022

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47. Xiao H, Zhang Y, Kong D, Li S, Yang N. The effects of social support on
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The psychological impact, risk factors and coping strategies to COVID-19 pandemic on healthcare workers in the sub-Saharan Africa: a narrative review of existing literature

Abstract

Background:

Methods:

Result:

Conclusion:

Introduction

Methodology

Search methodology and article selection

Search processes

Eligibility criteria

Data extraction and appraisal of the study

Definition of healthcare worker (HCW)

Results

Search results

Study characteristics

Risks of bias and confounding factors

Socio-demographic factors

Age

Gender

Psychological impact on healthcare workers

Risk factors associated with adverse mental health outcomes

Occupational factors

Healthcare groups

Frontline staff with direct contact with COVID-19

Lack of personal protective equipment (PPEs)

Heavy workload

Psychosocial factors: perceived stigma and fear of infection

family concerns

Protective psychosocial factors

Safety of family

Underlying illnesses

Protective factors against adverse mental health outcomes

Protective occupational factors

Experience

Trainings

Adequate supply of PPEs

Discussion

Overview of the study sites

High prevalence of psychological disorders among participants

Risk factors of psychological disorders among participants

Regional variations of psychological disorders

Socio-demographic characteristics

Regular monitoring of high-risk groups

Social support and coping mechanisms

Protective and coping measures

Future research direction

Limitations of this study

Conclusion

Acknowledgements

References

CASE REPORT

Corresponding Author: E. Karaoz

Department of Histology and Embryology, Faculty of Medicine, Istinye University, Istanbul, Turkey

Tel: +902129998099, Fax: +728188291209, E-mail address: ekaraoz@hotmail.com

Copyright © 2022 Tehran University of Medical Sciences. Published by Tehran University of Medical Sciences
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International license (https://creativecommons.org/licenses/by-
nc/4.0/). Non-commercial uses of the work are permitted, provided the original work is properly cited

A Case of Non-Progressive Congenital Myopathy: Efficacy and Clinical

Outcomes of the Wharton’s Jelly Derived Mesenchymal Stem Cell

Transplantation

Riza Azeri1,2, Eda Sun3,4, Erdal Karaoz3,4,5

1 Department of Physical Therapy and Rehabilitation, Liv Hospital, Istanbul, Turkey

2 Department of Physiotherapy and Rehabilitation, Faculty of Health Science, Istinye University, Istanbul, Turkey

3 Department of Histology and Embryology, Faculty of Medicine, Istinye University, Istanbul, Turkey

4 Center for Stem Cell and Tissue Engineering Research and Practice, Istinye University, Istanbul, Turkey

5 Center for Regenerative Medicine and Stem Cell Research and Manufacturing, Liv Hospital, Istanbul, Turkey

Received: 12 Aug. 2021; Accepted: 14 Mar. 2022

Abstract- Non-Progressive Congenital Myopathy is a disease characterized by muscle weakness, and

unfortunately, there is no conventional treatment. In the last decade, regenerative medicine practices have

become a rising value, and Mesenchymal Stem Cells (MSCs) have fascinating outcomes in regenerative

medicine with their high regenerative capacities, their ability to regulate with paracrine secretions, and their

immunological properties. Based on our experience in our previous clinical studies, Wharton’s-Jelly-derived

(WJ-)MSCs are the most suitable source for muscle diseases among all MSC sources. In this study, we

evaluated the outcomes of 10 doses of WJ-MSC transplantation to the patient diagnosed with Non-Progressive

Congenital Myopathy. A 17-year-old female with a SPEN-1 mutation, Non-Progressive Congenital Myopathy

patient received 10 times as 1×10⁶ /kg in the intra-arterial, intramuscular and intravenous administration of

allogenic WJ-MSC. Before and after the treatment, the patient was followed-up with the upper extremity scale,

Vignos lower extremity scale, muscle strength scale, functional independence measure, and evaluation of

Serum creatine kinase (CK) levels. Improvement in both upper extremity scale and Vignos lower extremity

scales, increasing in muscle strength, and decreasing in CK-level were detected. Although transplantation of

WJ-MSC cannot treat any genetic-based diseases, they may benefit in alleviating clinical outcomes of disease.

More importantly, WJ-MSC transplantation may offer a better quality of life by alleviating the symptoms of

this rare disease with no treatment option that can be provided in conventional methods.

Acta Med Iran 2022;60(4):249-253.

Keywords: Non-progressive congenital myopathy; Mesenchymal stem cells; Muscle fibrosis; Muscle-fiber

regeneration

Introduction

Non-progressive-congenital-myopathy is a muscular

disorder characterized by hypotonia, motor development

retardation, and proximal muscle weakness without any

conventional treatment. Pathophysiology of congenital

myopathy is related to protein defects that play a

significant role in skeletal muscle contraction via their

interaction with myosin, calcium homeostasis of skeletal

muscle, or sarcomere proteins in skeletal muscle (1).

Mesenchymal stem cells (MSC) are emerging

biological sources used in regenerative medicine with

their capacity for self-renewal, differentiation potential,

anti-inflammatory, antiapoptotic, regenerative, and

immunomodulatory abilities, and the preferable cellular

source for therapeutic applications (2). MSC can be

derived from different sources (3); Wharton-jelly-derived

MSC(WJ-MSCs) are promising therapeutic sources for

Wharton’s jelly derived mesenchymal stem cell transplantation to a non-progressive congenital myopathy

250 Acta Medica Iranica, Vol. 60, No. 4 (2022)

the treatment of myopathies by preventing muscle cell

death via repressing apoptosis (3) with their paracrine

activity such as secreting cytokines, releasing exosomes,

and reaching the damaged host cells and by repopulating

promote muscle regeneration and so improved muscle

function and pathology (4).

The cellular therapy for non-progressive congenital

myopathy using allogenic MSCs underlies the

improvement of myogenic differentiation (5) reverses

myopathy via increasing the satellite cell pool. This

clinical study aimed to consider the efficacy of allogeneic

WJ-MSC treatment for the rare disease of non-

progressive-congenital-myopathy.

Case Report

A 17-year-old female patient got diagnosed with non-

progressive-congenital-myopathy with a muscle biopsy

at the age of 10 was treated. Histological sections showed

a slight diameter difference between muscle fibers,

atrophy, several regenerated fibers, and rare central nuclei

fibers. There was a significant increase in the prismatic

adipose tissue and a focal increase in the endomysial

connective tissue. Spectrin, merosin, dystrophin (1,2,3),

alpha, beta.

üçç, gamma, and delta sarcoglycan were positive in

immunohistochemistry staining also confirmed

myopathic changes.

This patient had a homozygous deletion in the 6th exon

of the SPEN1 gene, and her healthy mother-father-brother

was heterozygous for the same deletion. The study was

approved by the Ethical Committee of the Ministry of

Health Republic of Turkey (protocol

number:56733164/203), was performed in accordance

with the Helsinki Declaration, and informed consent was

received from the patient’s family.

The patient was treated with allogeneic WJ-MSC with

a total of ten doses with four additional doses as 1×106/kg

once a month. The treatment was initially planned as 6

doses. The three doses (1st,4th, and 6th) were planned the

combination of intra-arterial, intra-muscular, and intra-

venous; the other three doses (2nd,3rd, and 5th) of

intramuscular injections of WJ-MSC into abdominal

muscles, deltoid, quadriceps, tibialis anterior and gluteal

muscles by using ultrasonography (Figure 1). Nine

months after 6 doses of planned therapy, an increase in

Creatine Kinase (CK) level was detected. So, we decided

to add additional 4 doses of WJ-MSc transplantations by

following the first treatment protocol design.

Figure 1. Designing and timeline of stem cell transplant therapy for Non-Progressive Congenital Myopathy patient

Transplanted MSCs were isolated, expanded, and

characterized based on our previous protocols (6). These

tests results were detected in the reference range required

for transfer to the patient (Figure 2).

R. Azeri, et al.

Acta Medica Iranica, Vol. 60, No. 4 (2022

)

251

Figure 2. A) Flow cytometer analysis of WJ-MSC. A1; Positive expressions of CD90, CD105, CD44, CD73 markers and A2; negative

expressions of CD45/34/11b/HLA DR/19 marker cocktail. B) Gene expression profile of WJ-MSC. C) Mycoplasma PCR results on the agarose gel.

M: M: DNA ladder; 1: positive control; 2: negative control; 3: donor

The efficacy of allogeneic WJ-MSC treatment for our

patient was evaluated by five clinical evaluation test

parameters pre-/post-treatment measurements; Brooke

upper extremity scale, Vignos lower extremity scale,

muscle strength scale, functional independence measure,

and evaluation of Serum creatine kinase (CK) levels.

Based on comparison measurements taken at the pre-

and the post-term of treatment, the patient’s Brooke upper

extremity scale had decreased from 6 to 3. When the

general condition of the patient is evaluated, it was not

possible or even difficult to do daily hand skill activities

before the treatment. It was seen that there was little

difficulty or no difficulty in individual skills such as

writing, combing hair, eating after the treatment. The

Vignos lower extremity scale had dropped from 10 to 5,

so the patient showed improvement in independent

walking. It was recorded that the 6-meter area walked in

95 steps and approximately 2 minutes after the treatment,

while it was difficult to take 3-4 steps before the

treatment. The muscle strength scale elevated from 1 to

3, so there was a significant increase in muscle strength.

The functional independence measure was increased

from 3 to 27 out of 40. The patient has become capable of

activities that are restricted before the treatment, such as

dancing, rarely sitting at the table, eating, walking around

the house, writing, and writing. Although the CK level

was decreased from 232U/L to 140U/L, 9 months after

the treatment, it increased to 408U/L again. After the four

additional doses, the CK level was re-declined to 136 U/L

(Figure 3).

Wharton’s jelly derived mesenchymal stem cell transplantation to a non-progressive congenital myopathy

252 Acta Medica Iranica, Vol. 60, No. 4 (2022)

Additionally, no serious side effects were observed in

the patient, who was observed by physicians on-site

consistently throughout the study.

Figure 3. Overall results of the evaluations tests. A) Total scale assessment of muscle function tests. B) The results of CK level after MSC

injections

Discussion

Our patient, diagnosed with Non-progressive

congenital myopathy, is a rare disease, got a homozygous

deletion in the SPEN1 gene at the 6th exon that causes

embryonic lethality due to defects in many vital tissue and

organ system formations, including the muscles (7).

Combining both the genetic background and the clinical

outcomes of the patient, SPEN1 mutations cause atrophy

of the adductor magus and biceps femoris muscles, which

have a major role in the grade of walking ability. As seen,

the increase in the Vignos-scale in post-treatment showed

the patient started walking without support. Likewise, it

has been reported that the CK levels in SPEN1 related

muscle disorders were measured 300-500IU/L (8).

Considering the effect of the increase in CK level causes

inflammation and necrosis of myofibers, the decrease in

CK level after allogenic WJ-MSC transplantation would

support the regression of the effects of the disease. As

seen in Figure 3, the CK level peaked again between the

6th dose and the additional 1st doses. Although each dose

was injected in monthly doses on average, the interval

between these 2 doses is 9 months. This gap reversed the

CK level with the increase of fibrosis. Decreasing with

the additional doses can be explained by immune evasive

and anti-inflammatory characteristics of MSCs via

suppressing T-cell functions by secreting PGE2,

secreting anti-inflammatory cytokines such as IL-10,

increasing the secretion of TNF-, IL1 and IL1 (6).

However, the increase in CK level shows us that repeated

MSC injections in genetic-based muscle disease are how

important and necessary.

One of the important factors determining the

effectiveness of the treatment depends on the

transplantation route of MSCs. Our cellular therapy for

this case was designed as three different transplantation

routes intra-arterial, intramuscular and intravenous. The

reason for choosing these routes were the anti-

inflammatory effects of both intramuscular and

intravenous injections; by the intramuscular injection, a

local regeneration as the lost tissue caused by the disease

triggers differentiation and triggers the formation of new

myofibrils can be provided (9), and a wider systemic

effect of intra-arterial (10).

The use of MSCs in the treatment of irreversible

muscle diseases has a significant place in regenerative

medicine. According to the National Institute of Health

Clinical Trials data, the importance of using MSC in the

translational treatment of muscular diseases is increasing.

There are 13 MSC treatment records for myopathy or

muscular disorders; four of them are WJ-MSC. This

increased acceleration of preferring WJ-MSC for muscle

diseases is the triggering proliferation by anti-apoptotic

effect, endogenous muscle cell precursors, and its

immunosuppression role for preventing fibrosis through

on myofibroblast via regulating the Extra Cellular Matrix

via its paracrine secretions (2,3). Besides the paracrine

secretions, MSCs also transfer their genomic material. As

we report, the 10-Duchenne Muscular Dystrophy patients

treated with WJ-MSC showed the restoring dystrophin

expression by cellular fusions explained by fusing with

the recipient cells to transfer its genomic material. So, the

deteriorated gene expression pattern related to the

myogenic differentiation may be impaired by SPEN1

might be regulated (6).

WJ-MSC transplantation may offer a better quality of

A) B

)

R. Azeri, et al.

Acta Medica Iranica, Vol. 60, No. 4 (2022) 253

life by alleviating the symptoms of this rare disease with

no treatment option that can be provided in conventional

methods. Although transplantation of WJ-MSC cannot

treat any genetic-based diseases, they may offer a more

comfortable life with slowing the progression rate,

regression of fibrosis, and immunoregulation (6). For all

that, new technologies, such as CRISPR/Cas9, might be

offering advanced these MSCs therapies with combining

the gene-editing approaches in the years to come.

Acknowledgments

The authors acknowledge Gökay Görmeli, Assoc.

Prof. Dr.; Sacit Karamürsel, Prof. Dr. and Gülşen Günel,

MSc. for their technical and clinical assistance.

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Findings in the Area of Mesenchymal Stem Cells Reported
from Beijing Hospital (Human Umbilical Cord Mesenchymal
Stem Cell-derived Conditioned Medium Promotes Human
Endometrial Cell Proliferation Through Wnt/beta-catenin
Signaling).
Date: Nov. 17, 2022
From: Women’s Health Weekly
Publisher: NewsRX LLC
Document Type: Report
Length: 542 words

Full Text:
2022 NOV 17 (NewsRx) — By a News Reporter-Staff News Editor at Women’s Health Weekly — Investigators publish new report on
Stem Cell Research – Mesenchymal Stem Cells. According to news reporting from Beijing, People’s Republic of China, by NewsRx
journalists, research stated, “Mesenchymal stem cells (MSCs) and their derivant are among the promising treatments for intrauterine
adhesion (IUA); they have been reported to repair the endometrial injury by proliferating endometrial cells. However, the signal
pathways involved are not clear.”

Financial support for this research came from Beijing Dongcheng Department of Science, Technology.

The news correspondents obtained a quote from the research from Beijing Hospital, “This study investigated the role of human
umbilical cord mesenchymal stem cell-derived conditioned medium (hUCMSC-CM) in relieving IUA to find out whether Wnt/beta-
catenin signaling was involved, and if so, to determine the possible ligands. After endometrial epithelial cells (EECs) were treated with
hUCMSC-CM, their proliferation and migration were measured by the CCK8 assay and the scratch assay. The activation of Wnt/beta-
catenin signaling was measured by Western blots, fluorescent staining, and T-cell factor/lymphoid enhancer factor (TCF/LEF)
luciferase. A Wnt inhibitor (XAV393) was used to inhibit the proliferation effect of hUCMSC-CM in EECs. Wnt5a expression in
hUCMSC was measured by Western blots and fluorescent staining, and Wnt5a in hUCMSC-CM was detected by enzyme-linked
immunosorbent assay (ELISA), to further clarify the mechanism. As shown by the CCK8 assay, hUCMSC-CM promoted proliferation
and migration of EECs. The expression of beta-catenin, c-myc, and cyclin D1 increased in EECs after being treated with hUCMSC-
CM. Moreover, hUCMSC-CM was found to promote beta-catenin delivery into nuclei by Western blot and fluorescent staining;
meanwhile, the inhibitor (XAV393) could restrain this process and inhibit the effect of hUCMSC-CM on EEC proliferation. Wnt5a was
detected in hUCMSCs and hUCMSC-CM, which might be a potential therapeutic target. This study demonstrated that hUCMSC-CM
promoted human endometrial cell proliferation through Wnt/beta-catenin signaling, and Wnt5a might be a potential activator.”

According to the news reporters, the research concluded: “This would be one of the activating signal pathways in the MSC-related
treatment of IUA.”

For more information on this research see: Human Umbilical Cord Mesenchymal Stem Cell-derived Conditioned Medium Promotes
Human Endometrial Cell Proliferation Through Wnt/beta-catenin Signaling. BioMed Research International, 2022;2022. BioMed
Research International can be contacted at: Hindawi Ltd, Adam House, 3RD Flr, 1 Fitzroy Sq, London, W1T 5HF, England.

Our news journalists report that additional information may be obtained by contacting Shaowei Wang, Chinese Academy of Medical
Sciences, Beijing Hospital, Inst Geriatr Med, National Center of Gerontology, Beijing, People’s Republic of China. Additional authors
for this research include Xiaoning Wei, Sichen Zhang, Xinyu Xu, Feiran Liu, Jin Li, Qingyu Wang and Jianping Cai.

Keywords for this news article include: Beijing, People’s Republic of China, Asia, Armadillo Domain Proteins, Catenins, Cell
Proliferation, Gynecology, Health and Medicine, Mesenchymal Stem Cells, Proteins, Stem Cell Research, Transcription Factors,
Women’s Health, beta Catenin, Beijing Hospital.

The citation for this news report is: NewsRx. Findings in the Area of Mesenchymal Stem Cells Reported from Beijing Hospital (Human
Umbilical Cord Mesenchymal Stem Cell-derived Conditioned Medium Promotes Human Endometrial Cell Proliferation Through
Wnt/beta-catenin Signaling). Women’s Health Weekly. November 17, 2022; p 2356.

Copyright: COPYRIGHT 2022 NewsRX LLC
http://www.newsrx.com/newsletters/Womens-Health-Weekly.html
Source Citation (MLA 9th Edition)
“Findings in the Area of Mesenchymal Stem Cells Reported from Beijing Hospital (Human Umbilical Cord Mesenchymal Stem Cell-

derived Conditioned Medium Promotes Human Endometrial Cell Proliferation Through Wnt/beta-catenin Signaling).” Women’s
Health Weekly, 17 Nov. 2022, p. 2356. Gale OneFile: Business,
link.gale.com/apps/doc/A726409342/GPS?u=lirn50909&sid=bookmark-GPS&xid=6f31cad6. Accessed 7 Feb. 2023.

Gale Document Number: GALE|A726409342

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CASE REPORT Open Access

An unusual hematopoietic stem cell
transplantation for donor acute
lymphoblastic leukemia: a case report
Di Zhou†, Ting Xie†, Suning Chen2, Yipeng Ling1, Yueyi Xu1, Bing Chen1, Jian Ouyang1 and Yonggong Yang1*

Abstract

Background

: Donor acute lymphoblastic leukemia with recipient intact is a rare condition. We report a case of
donor developing acute lymphoblastic leukemia 8 yrs after donating both bone marrow and peripheral blood
hematopoietic stem cells.

Case presentation

: This case report describes a 51-year old female diagnosed with acute lymphoblastic leukemia
who donated both bone marrow and peripheral blood stem cells 8 yrs ago for her brother with severe aplastic
anemia. Whole exome sequencing revealed leukemic genetic lesions (SF3B1 and BRAF mutation) only appeared in
the donor sister, not the recipient, and an unusual type of hematopoietic stem cell transplantation with the
recipient’s peripheral blood stem cells was done. The patient remained in remission for 3 months before disease
relapsed. CD19 CAR-T therapy followed by HLA-identical unrelated hematopoietic stem cell transplantation was
applied and the patient remains in remission for 7 months till now.

Conclusions: This donor leukemia report supports the hypothesis that genetic lesions happen randomly in
leukemogenesis. SF3B1 combined with BRAF mutation might contribute to the development of acute
lymphoblastic leukemia.

Keywords: Donor leukemia, Acute lymphoblastic leukemia, Hematopoietic stem cell transplantation, SF3B1, BRAF

Background
Donor leukemia is a rare condition and only anecdotal
reports described its development [1, 2]. There are two
types of donor leukemia, literally the donor itself devel-
oping leukemia or donor cells in the recipient develop-
ing leukemia (Donor Cell Leukemia, DCL), which is
more commonly reported. Two mechanisms have been
proposed for DCL development: occult transfer of malig-
nant cells from donors during hematopoietic stem cell
transplantation (HSCT) or leukemic transformation of

healthy donor cells in recipients [3–6]. The latter one is
unpredictable but it takes up the majority of DCL.
Donor developing leukemia with recipient intact is even
a rarer condition and only few reports described the de-
velopment of acute myeloid leukemia (AML), not acute
lymphoblastic leukemia (ALL), in peripheral blood stem
cell (PBSC) donors [7, 8]. G-CSF administration was sus-
pected for leukemogenesis but there have been no valid
evidence to support the hypothesis. Meanwhile, there
have been no reports describing the development of
ALL in hematopoietic stem cell donors, not recipients.
Here we reported a case with only the donor develop-

ing ALL 8 yrs after donating hematopoietic stem cells
but not the recipient. Whole exome sequencing (WES)
showed leukemic genetic lesions (SF3B1 and BRAF mu-
tation) only appeared in the donor’s hematopoietic cells.

© The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License,
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appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if
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licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain
permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the
data made available in this article, unless otherwise stated in a credit line to the data.

* Correspondence: 915834491@qq.com
†Di Zhou and Ting Xie are co-first authors
1Department of Hematology, The Affiliated Drum Tower Hospital of Nanjing
University Medical School, 321 Zhongshan Road, Nanjing 210008, People’s
Republic of China
Full list of author information is available at the end of the article

Zhou et al. BMC Cancer (2020) 20:195
https://doi.org/10.1186/s12885-020-6681-2

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mailto:915834491@qq.com

A special type of HSCT using the recipient’s PBSCs was
done. To our knowledge, this is the first case report of
donor developing ALL and an unusual type of HSCT.
We hope it could provide more evidence for donor
leukemia formation and the potential role of SF3B1 and
BRAF mutation in ALL.

Case presentation
In May 2017, a 51-year old female presented to our hos-
pital with over 1 week of fatigue. She has medical history
of donating both bone marrow and PBSCs 8 yrs ago for
her brother with severe aplastic anemia (SAA). G-CSF
was used to mobilize hematopoietic stem cells for PBSC
collection. Complete blood count (CBC) showed lym-
phocytosis (Lymphocyte 10*10^9/L), moderate anemia
(Hb 61 g/L) and thrombocytopenia (PLT 20*10^9/L).
Peripheral blood smear demonstrated 30% of blast cells.
Bone marrow biopsy showed lymphoblastic leukemia in-
volving a markedly hypercellular marrow (Fig. 1). Flow
cytometry showed the blasts expressed CD10, CD19,
CD22, CD38, HLA-DR, but not CD13, CD33, CD117, or
cytoplasmic MPO. Chromosomal analysis showed a nor-
mal female karyotype. The diagnosis of B-ALL was
made. VDP regimen (Vindesine, Daunorubicin, Prednis-
one) was started after her diagnosis and bone marrow
aspirate 14 days later revealed complete remission (CR).
Then 2 cycles of VDLP regimen (Vindesine, Daunorubi-
cin, Prednisone, Pegaspargase) and 2 cycles of MA
(Mitoxantrone, Cytosine arabinoside) + Pegaspargase
(PEG-Asp) regimen were administered. During this
period, the patient remained in remission and cerebro-
spinal fluid (CSF) remained clear after intermittent four
time lumbar punctures. Minimal residue disease (MRD)
monitoring by flow cytometry after each cycle did not
detect blast cells with abnormal phenotype. Considering
she has no other HLA-identical siblings or unrelated do-
nors from China Bone Marrow Bank at that time and
her brother, who was perfectly stable, a special type of

auto-HSCT using her brother’s PBSCs was performed in
December 2017. Before the transplantation, whole ex-
ome sequencing (WES) was done for both the donor
and recipient to rule out occult genetic abnormalities in
the stem cells. Results showed that only the patient, not
her brother, has genetic mutations including SF3B1 and
BRAF mutation associated with hematological malignan-
cies in her hematopoietic cells, not oral mucosal cells
(Table 1) [9–11]. Myeloablative conditioning regimen
(Melphalan 140 mg/m2 d-3/d-2/d-1, Cytarabine 1 g/m2

d-3/d-2, Cyclophosphamide 60mg/Kg d-3/d-2) was
used. A total of 2.34*10^6/kg CD34+ cells, 13.0*10^8/kg
MNCs from peripheral blood were collected and trans-
fused into the patient. Neutrophil engraftment occurred
at day + 11 and platelet engraftment occurred at day +
14. VP regimen (Vindesine, Prednisone) and MTX + 6-
MP regimen were used for maintenance therapy. Bone
marrow aspirate and flow cytometry showed that the pa-
tient remained in complete remission 3 months after
transplantation. In May 2018, the patient’s CBC showed
leukocytosis and bone marrow aspirate indicated disease
relapsed with 53.33% blast cells. Flow cytometry showed
the blasts expressed CD10, CD19, HLA-DR and partially
expressed CD11b. Genetic testing using polymerase
chain reaction (PCR) technique found that SF3B1 and
BRAF exome mutation was negative. Re-induction
chemotherapy with VDP regimen was administered, the
patient achieved CR. However, after another 2 cycles of
high-dose MTX+ PEG-Asp regimen, disease relapsed. In
November 2018, CD19 CAR-T therapy followed by
HLA-identical unrelated hematopoietic stem cell trans-
plantation was applied and the patient remains in remis-
sion for 7 months till now.

Discussion and conclusion

Leukemogenesis is a complex process involving accumu-
lation of genetic changes in self-renewing hematopoietic
stem cells (HSCs) [12]. Two-hit model was proposed for

Fig. 1 Bone marrow biopsy of the patient showed a markedly hypercellular marrow implying ALL

Zhou et al. BMC Cancer (2020) 20:195 Page 2 of 5

the clonal evolution of leukemia [13]. Genome sequen-
cing indicated that most mutations in the leukemia gen-
ome were random events and the acquirement of one or
two initiating mutations generated the founding clone
for leukemogenesis [14]. In this case, a careful review of
the medical history of both the brother and sister
showed that there were no noteworthy differences in
hazard substance exposure. During HSCT, the brother
was exposed to more cytotoxic drugs, including CTX,
MTX, CsA, while the sister was only exposed to short-
time G-CSF before she developed ALL. WES revealed
leukemic alterations including SF3B1 and BRAF muta-
tion only happened in the donor sister. So we assumed
that development of these mutations in her
hematopoietic stem cells, not oral mucosal cells, were
probably random events.
SF3B1 gene is located at chromosome 2q33.1 and the

encoded protein is an essential component of the U2
small nuclear ribonucleoproteins complex (U2 snRNP),
which functions by splicing pre-mRNAs. SF3B1 muta-
tion often occurs in melanoma, chronic lymphocytic
leukemia (CLL) or myelodysplastic syndrome (MDS)

[15]. Quesada et al. found that SF3B1 mutation could
possibly alter its normal function by changing the phys-
ical interactions with its binding partners [16]. Of note,
U2 snRNP with mutated SF3B1 could affects the splicing
of FOXP1 pre-mRNA resulting in the expression of
truncated FOXP1 protein, which has been implicated in
diffuse large B-cell lymphoma [17]. In this case, WES
found SF3B1 R625H mutation in the patient’s blood cells
but there have not been reports about the association
between SF3B1 mutation and ALL. Considering the mu-
tation could affect genes involved in malignant trans-
formation of B cells like FOXP1, in might participate in
the patient’s leukemogenesis.
BRAF gene is located at chromosome 7q34 and it en-

codes a member of the Raf kinase family which regulates
cell division, differentiation and secretion. More than 30
mutations of BRAF gene have been identified in human
cancers and V600E was most frequently found [18]. It is
a likely driver mutation in hairy cell leukemia and has
been widely observed in melanoma, Langerhans cell his-
tiocytosis, papillary thyroid carcinoma, colorectal cancer
and non-small-cell lung cancer [19]. BRAF mutations

Table 1 Genetic mutations in the sister’s hematopoietic cells (Sample A), oral mucosal cells (Sample B) and the brother’s
hematopoietic cells (Sample C) detected by WES

Gene Chrs Position Ref
Allele

Alt
Allele

Predicted Protein Variants

Genetic mutations shared by Sample A,B,
C

ARHGEF10L 1 18,014,104 G A V794M, V972M, V719M, V1016M,
V977M

YIF1B 19 38,798,111 T C Y234C, Y232C, Y249C, Y246C, Y218C

AMBRA1 11 46,529,825 C T R662H, R755H, R633H

ATRAID 2 27,438,205 T C C80R, C22R, C135R

CACNB3 12 49,212,737 G A G9R

IPO4 14 24,650,793 G C L991V

PLA2G15 16 68,293,133 C T P271L

ZNF574 19 42,582,813 T C S109P, S19P

NID2 14 52,505,486 T G N746H

ALG8 11 77,824,984 C T G242E

HOXB5 17 46,670,899 T C Y49C

TIE1 1 43,787,288 T G Y1083D, Y1038D

CACNA1F X 49,066,102 G C S1603C, S1614C, S1549C

FREM2 13 39,263,181 C G T567R

Genetic mutations shared by Sample A
and C

ZGRF1 4 113,506,711 C T E1305K, E1363K

SLC43A2 17 1,495,007 C T

CHM X 85,134,073–85,134,
073

– A

Genetic mutations specific to Sample A SF3B1 2 198,267,483 C T R625H

BRAF 7 140,481,411 C T G466E

ZC3H7B 22 41,742,094 G C R516P

LAMC1 1 183,077,450 C T R255C

Sample A: the sister’s hematopoietic cells; Sample B: the sister’s oral mucosal cells; Sample C: the brother’s hematopoietic cells

Zhou et al. BMC Cancer (2020) 20:195 Page 3 of 5

could change the activation segment from inactive state
into active state and enhance B-raf kinase activity, which
augment cell proliferation. However, in ALL the fre-
quency of BRAF mutation is very low and only V600E,
G468A, L597Q mutations have been reported [20–22].
Helene Cav et al. reported that children with Noonan
Syndrome, some of which harbor BRAF mutation, are at
higher risk of developing ALL [23]. In this case, we
found BRAF G466E in the patient, not her brother. It
might form double hits with SF3B1 mutation, which
could affect genes involved in pre-B cell differentiation,
and ultimately leads to leukemogenesis in this patient.
More basic research needs to be done to clarify the
mechanism.
ZC3H7B and LAMC1 gene mutations were also found

in the patient’s hematopoietic cells, but there have been
no reports of them in hematological malignancies. Their
roles in leukemogenesis still need to be uncovered.
G-CSF is used in the majority of allogeneic

hematopoietic stem cell donations. Some studies showed
its application was associated with increased risk of later
development of MDS/AML [6, 8]. Meanwhile, some
other studies failed to identify the correlation [24, 25]. It
is a critical issue but it remains controversial. In our
case, the donor developed ALL 8 yrs after hematopoietic
stem cell mobilization using G-CSF. Her leukemogenesis
and G-CSF usage were probably irrelevant since G-CSF
is a regulator for granulopoiesis, not lymphopoiesis. The
duration and dosage of G-CSF administration was longer
and higher in the recipient brother, but till now no signs
of MDS/AML have been detected in him. Therefore,
high quality and more conclusive clinical data is needed
to clarify G-CSF usage and leukemia formation espe-
cially in healthy donors.
The suspicion of delayed onset of DCL was also con-

sidered. According to previous reports of DCL, the aver-
age latent period is within 4 yrs of HSCT [26, 27]. In
our case, the recipient brother did not develop leukemia
8 yrs after transplantation. Additionally, WES showed no
leukemia-associated gene mutations in him and it fur-
ther ruled out the possibility of delayed leukemia onset.
Auto-HSCT can be considered in MRD negative ALL

patients without appropriate HLA-identical donors. In
this case, a special type of auto-HSCT was performed.
Compared with stem cells collected from the patient
herself, peripheral blood stem cells from her brother
were leukemia cell free and it was supposed to lower the
risk of disease relapse. However, the patient relapsed 3
months after transplantation. Since SF3B1 and BRAF
mutation turned negative after disease relapsing, we hy-
pothesized that leukemia sub-clones outgrew and caused
disease relapse.
To our knowledge, this is the first case report with

only donor developing ALL but not the recipient and

this is also the first report of an unusual type of auto-
HSCT. We hope it could provide more evidence for the
double-hit model in leukemogenesis and a potential al-
ternative for donor leukemia treatment.

Abbreviations

ALL: Acute Lymphoblastic Leukemia; Allo-HSCT: Allogenic Hematopoietic
Stem Cell Transplantation; AML: Acute Myeloid Leukemia; ATG: Anti-
Thymocyte Globulin; Auto-HSCT: Autologous Hematopoietic Stem Cell
Transplantation; CsA: Cyclosporine A; CSF: Cerebrospinal Fluid;
CTX: Cyclophosphamide; DCL: Donor Cell Leukemia; G-CSF: Granulocyte-
Colony Stimulating Factor; GVHD: Graft Versus Host Disease;
HSC: Hematopoietic Stem Cell; MNC: Mononuclear Cell; MTX: Methotrexate;
PBSC: Peripheral Blood Stem Cell; PCR: polymerase chain reaction;
SAA: Severe Aplastic Anemia; U2 snRNP: U2 small nuclear ribonucleoproteins
complex; WES: Whole Exome Sequencing

Acknowledgements

The authors would like to thank all the staff from the Department of
Hematology, Drum Tower Hospital for their helpful suggestions when
preparing this manuscript.

Authors’ contributions

DZ wrote this manuscript. TX, YL and YX collected and analyzed patients’
clinical data. SC analyzed the WES result. JO, BC and YY were responsible for
the treatment of patients. All Authors have read and approved the
manuscript.

Funding

No founding was received.

Availability of data and materials

The clinical data used or analyzed in this case report are available from the
corresponding author on reasonable request.

Ethics approval and consent to participate

Patients provided written informed consent for genetic analysis based on
the Declaration of Helsinki and were informed of the existence of other
treatment options in accordance with the Ethics Committee of Drum Tower
Hospital, the Affiliated Hospital of Nanjing University Medical School.

Consent for publication

Written informed consent was obtained from the patient for publication of
this case report and accompanying images.

Competing interests

The authors declare that they have no competing interests.

Author details

1Department of Hematology, The Affiliated Drum Tower Hospital of Nanjing
University Medical School, 321 Zhongshan Road, Nanjing 210008, People’s
Republic of China. 2Jiangsu Institute of Hematology, First Affiliated Hospital
of Soochow University, Suzhou, People’s Republic of China.

Received: 19 August 2019 Accepted: 26 February 2020

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Background

Case presentation

Conclusions