Elena Rusyn, MD, PhD, ABAARM

The Dark Side of Umbilical Stem Cells

Using Stem Cells Derived from Unrelated Donors

Stem cells regenerative medical field is truly a new era in medicine.

There are stem cells of different origin. I want to talk about stem cells derived from other sources than our own body. This treatment is called allogeneic stem cell transplant.

Celebrities are doing a wonderful job of spreading the word about stem cells but they believe it is safe to pour younger person’s blood or stem cells from pregnant female into their systems. Why? Because they been told so.  

There is a lot of confusing partial information that makes it a challenging to know your risks when you are thinking about having a stem cell procedure. Autologous or allogeneic?  

Using stem cells derived from unrelated donors (allogenic stem cells, not your own body) carries certain risks.  

An allogeneic stem cell transplant is different from an autologous stem cell transplant, which uses stem cells from the patient's own body.

I believe umbilical and amniotic stem cells should stay in neonatal hematology and pediatrics where a low number of stem cells can be very efficient in treating genetic metabolic and hematologic diseases and work great for preterm infants. In adult patients, blood malignancies and diseases are the common reason for using umbilical cord stem cells.

People who want to use stem cell therapy for other reasons should stay away from any stem cells that are not produced in their own body.

Here is what the literature says:

Over the past decades, umbilical cord-blood (CB) and amniotic tissues became a well-recognized alternative source of stem cells for unrelated donor hematopoietic stem cell transplantation. As compared with other allogeneic stem cell sources from adult donors, it has the advantages of immediate availability of cells, an absence of risk to the donor and reduced risk of graft-versus-host disease despite donor-recipient HLA mismatch.  

Unfortunately, Umbilical Cord Blood Transplant (UCBT) has several limitations, in particular, those associated with the prolonged period of neutropenia and the delayed immune reconstitution that has been related with a high transplantation-related mortality rate, up to 50% in several historical series.(1,2) As a result, infections remain the leading cause of morbidity and mortality during the first six months after transplantation.

As with any blood transfusion, umbilical cord and amniotic derived stem cells are a possible source of disease transmission. A myriad of agents can potentially be transmitted including bacteria, viruses, and parasites.  

A multitude of bacterial microorganisms has been isolated from contaminated blood products. The Bacthem study, BaCon study, and SHOT program found a similar range of microorganisms: Yersinia, Proteus, Pseudomonas, Escherichia, Klebsiella, Acinetobacter, and Serratia, Propionibacterium, Staphylococcus, Bacillus, and Enterococcus , Propionibacterium acnes, coagulase-negative staphylococci, Yersinia enterocolitica.

Transmittable Viral Infections include:

• Human immunodeficiency virus (HIV-1 and HIV-2)

• Hepatitis viruses :

HBV Viral Hepatitis B

HCV Cirrhosis Liver - Late Carcinoma Liver

Hepatitis A and E viruses

• West Nile virus ( Japanese encephalitis)

• Herpes viruses: Cytomegalovirus (CMV: hepatitis, lymphadenopathy, rashes, Intrauterine infection of newborns), HHV-8

• Human T-cell lymphotrophic viruses (HTLVs: Adult Cell Leukemia).Infection with these retroviruses may result in HTLV-related myelopathy/tropical spastic paraparesis (HAM/TSP) and adult T-cell leukemia/lymphoma.

• Parvovirus B19 (is a virus that is usually transmitted by the respiratory route and that eventually infects hematopoietic cells. The virus is also transmitted vertically from mother to child and via blood products. The parvovirus may cause bone marrow failure in immunocompromised patients and patients with sickle cell disease.

• Epstein Barr Virus

• Arboviruses (dengue viruses (DENV), chikungunya virus (CHIKV), and zika virus (ZIKV),

• Hepatitis G virus (HGV) and transfusion-transmitted virus (TTV) also have been shown to be transmissible via blood. The clinical impact of their transmission on a larger scale has still to be deciphered.

The federal regulations and require that all donors must be tested only for the following diseases:

• HBV and HCV

• HIV-1 and HIV-2

• HTLV-1 and HTLV-2

• Syphilis

• WNV

• Chlamydia trachomatis

• Neisseria gonorrhea

That does not cover the whole spectrum of transmittable diseases.

Protozoal organisms that can be passed on through transfusion include Plasmodium, which causes malaria and Babesiosis (tick-borne illnesses). There are 5 species of Plasmodium that can be transmitted:

• P falciparum

• P malariae

• P ovale

• P vivax

• P knowlesi

Prions, which cause Creutzfeldt-Jakob disease ("Mad Cow"), are also transmissible through transfusion; they cannot be destroyed using current techniques for inactivating pathogens in the blood supply.

The FDA website has the following recommendations: “Cord blood is approved only for use in “hematopoietic stem cell transplantation” procedures, which are done in patients with disorders affecting the hematopoietic (blood-forming) system. …Because cord blood contains stem cells, there have been stem cell fraud cases related to cord blood”. “Consumers may think that stem cells can cure any disease, but science doesn’t show this to be the case. Patients should be skeptical if cord blood is being promoted for uses other than blood stem cell regeneration.”

Mismatched donors (HLA-mismatch)

Regarding the use of unrelated and HLA- mismatched donors of Cord Blood and Amniotic stem cells/GVHD/Engraftment syndrome:

The human leukocyte antigen (HLA) system or complex is a gene complex encoding the major histocompatibility complex (MHC) proteins in humans. These cell-surface proteins are responsible for the regulation of the immune system in humans. The risk of having mismatched HLA genes in your transplant goes beyond the risk of acute or chronic graft-versus-host disease (GVHD), it is big disrupter of the immune system causing it’s chronic dysfunction that might have long-term side effects. Unfortunately, that is poorly studied because there is a lack of follow-up after a certain amount of time.  

HLA typing (matching) was studied mostly on patients with malignant diseases, however, it gives some insight into the importance of HLA matching when selecting Cord Blood (CB) donor units. In malignant diseases, HLA mismatching is partially overcome by competing for contributions graft-versus-Leukemia.  Retrospective HLA typing and the subsequent analysis revealed that concerning overall survival, while the level of original HLA match had no impact on the occurrence of aGVHD, if the pair were matched for fewer than 5/6 alleles there seemed to be a trend for survival advantage for 6/6 matched patients. The size of the cohort does not allow to draw definitive conclusions. The authors suggest selecting CB units that are at least 4 of 6 by typing at class I loci. Further analysis of larger series will provide more conclusive results regarding the impact of HLA matching on CBT.

On the other hand, for patients with non-malignant diseases, the use of unrelated CB from HLA-mismatched unrelated donor will require a larger study, regarding engraftment, survival, and GVHD.

(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3477523/)

High fevers and/or rashes are frequently observed after umbilical cord blood (UCB) transplantation, and the condition is referred to as pre-engraftment syndrome (PES)  

Engraftment syndrome (ES), characterized by fever, rash, pulmonary edema, weight gain, liver, and renal dysfunction, and/or encephalopathy, occurs at the time of neutrophil recovery following hematopoietic cell transplantation (HCT).

Whether ES and GVHD are distinct syndromes in the allogeneic context remains unclear. ES has commonly been described as a cytokine storm condition (3) or hyperacute GVHD.

Late Infections due to profound Immunosuppression

Bacterial Infections

Severe bacterial infections remain a leading cause of morbidity and non-relapse mortality, especially before day 100 in patients undergoing UCBT.(12,32,33) However, few studies have specifically addressed this issue in the UCBT setting.(30,33,34,35)

The reported incidence of bacterial infections ranged from 12% to 64% depending on the follow-up and the intensity of the conditioning regimen. Studies that were focused in the early/intermediate period (until day +100) reported an incidence ranging from 30 to 40%. (32,34) However, with longer follow-up, the incidence increased up to 50 to 70% at 4 years.(30,32)

These data suggest an increased predisposition to late infections after UCB Treated to the delayed immune reconstitution and/or the profound immunosuppression status following UCBT treatment.

Most studies have demonstrated a predominance of Gram-positive bacteria (GPB) bloodstream infections (BSI) occurring before day +100 (6,33,34,35) and in others within the first year post-transplant.14 Among the GPB, coagulase-negative staphylococcus (CoNS) were more common, followed by Enterococcus species. Among GNR, Escherichia coli and Pseudomonas spp. were the most frequently isolated bacteria (32% and 29% of GNR, respectively).(30) Several studies have identified risk factors associated with increased risk of infections after UCBT depicts neutropenia, the delayed lymphocyte recovery and in the profound immunosuppression status.(30,32, 37)

BSI in the UCBT has a negative impact on mortality. The death rate of bacterial infections in the early posttransplant period is around 25%, mostly due to GNR. Most frequent reported organisms causing fatal BSI were Acinetobacter spp., followed by Stenotrophomonas maltophilia, Klebsiella-Enterobacter-Serratia, Pseudomonas aeruginosa and Escherichia coli.(30,34.30,33)

Viral Infections

Viral disease (VD) markers including hepatitis B (HBV) and C (HCV), human immunodeficiency virus (HIV), human T-lymphotropic virus Types 1 and 2 (HTLV 1/2), and cytomegalovirus (CMV) are screened in all maternal blood samples of every UCB sample collected and stored as part of quality control dictated by international guidelines and according Accreditation Standards.

As a result, severe infectious complications continue to be a leading cause of morbidity and mortality following UCB transplantation (UCBT).

UCBT recipients are at increased risk of severe viral infections when compared with other graft sources, especially due to viral pathogens that require a strong T-cell immunity control such as for the herpes viruses family.18,45,46,47,48,49 In the current review, we summarize the most relevant viral infections in the UCBT setting: cytomegalovirus (CMV), Epstein-Barr virus (EBV) and human herpes virus-6 (HHV-6).

CMV

Patients receiving UCBT are at high risk of CMV infection and disease. Nevertheless, the incidence, outcome, and risk factors for CMV infection and illness after UCBT have been barely addressed. Only two retrospective studies have compared CMV infection and illness in UCBT or other stem cell sources.52,58

EBV

EBV reactivation and EBV associated post-transplantation lymphoproliferative disorder (EBV-PTLD) does not seem to be increased in UCBT compared to allogeneic bone marrow transplantation and peripheral blood stem cell transplants. The reported incidence of EBV viremia or PTLD in this setting is around 3–5%.(23,49,65)

EBV infection or reactivation is not a concern when it comes to autologous (your own) stromal vascular fraction containing your own stem cells.

The clinical course of EBV associated post-transplantation lymphoproliferative disorder was aggressive with high mortality despite the administration of rituximab or chemo-immunotherapy when feasible.(65,67–69)

HHV-6

HHV-6 reactivation is frequent after UCBT and can be detected in over 80% of patients early after transplantation.(45,70–74) The clinical significance of viral reactivation is unknown, although it has been associated with many complications including encephalitis, marrow suppression and delayed engraftment, skin rash, hepatitis, interstitial pneumonia and an increased risk of developing aGVHD. A recent meta-analysis showed an increased prevalence of HHV-6 reactivation and severity of HHV-6 associated disease in patients receiving UCBT in comparison to other stem cell sources, recommending a close monitoring for HHV-6 reactivation in this setting.(75) A more recent study investigated HHV-6 reactivation within 60 days of transplantation in stem cell transplants using single UCB, double UCB, or UCB plus haploidentical stem cells. Of 92 patients, 60 (65%) had HHV-6 reactivation. Reactivation was not significantly influenced by any patient characteristics, disease characteristics, or by stem cell source. Indeed, they did not observe any impact of HHV-6 reactivation on neutrophil or platelet count recovery or on relapse-free survival. However, HHV-6 reactivation was associated with subsequent development of acute GVHD

Fungal Infections

Again, studies focusing on invasive fungal infections (IFIs), both invasive candidiasis and invasive mold infections after UCBT are scarce.

Reported incidences of fungal infections ranged from 10% to 38%, of which 33%-100% occurred before day +50. Most common sites of IFI were invasive pulmonary infections followed by brain abscess and disseminated fungal infection. Of the sixty-three documented fungal infections published in the literature, 35 episodes of fungemia were caused by Candida, 19 by Aspergillus, 2 by Scedosporium, 2 by Zygomycetes, 1 by Cryptococcus, 1 by Saccharomyces, 1 by Fusarium, 1 by Trichosporon and 1 by Rhizopus.(6,12,13,14,30,36,37,41,42) A higher proportion of IFIs before day +100 after UCBT compared to bone marrow or peripheral blood stem cell transplantation has been suggested.(32)

Conclusions

Over the past three decades, remarkable progress has been made in the use of UCB and amniotic stem cells as an alternative stem cell source for allogeneic transplantation for patients lacking a suitable HLA-matched donor. However, UCBT is still limited by the low cell dose of the graft and the slow or incomplete immune reconstitution, resulting in high transplantation-related mortality (TRM) due to infections.

Efforts to improve graft selection, shorten neutropenia, enhance immune reconstitution and develop prevention and supportive care measures should be the primary focus of clinical research in the field.
 

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